Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development
Open accessAbstract
Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.
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Written from the paper’s full text.
TL;DR
Both autism/dyslexia-linked DOCK4 variants, Dock4-945VS and Dock4-R853H, impair Rac1 and Rap1 activation and fail to promote cell morphology changes, neurite outgrowth, and dendritic spine formation. R853H retains partial ability to enhance excitatory synaptic transmission, whereas 945VS loses it completely, identifying Arg853 as critical for Dock4 function.
Key findings
- Both mutants lost Rap1 activation; 945VS totally lost Rac1 activation, while R853H decreased activated Rac1 less robustly than 945VS. Dock4 KO hippocampus showed reduced Rap1-GTP (P < 0.05, unpaired t-test; three independent experiments).
- Domain mapping showed ΔSH3 could not activate Rap1, ΔC retained Rap1 activation, ELMO2 enhanced Dock4-FL Rap1 activation, SH3-F abolished it, and the RacGEF-dead AAA mutant lost Rac1 activation but retained Rap1 activation.
- In HEK293T/COS7 cells, WT Dock4 increased cell size and F-actin, whereas R853H and 945VS did not. In Neuro-2a cells and hippocampal neurons, neither mutant promoted neurite outgrowth compared with vector; WT did (at least 40 cells/group).
- In hippocampal neurons, WT Dock4 increased spine density and mushroom-shaped spines, but neither mutant did (at least 30 cells/group). mEPSC recordings showed WT increased amplitude and frequency; R853H increased them but weaker than WT; 945VS completely lost this ability (at least 10 cells/group). Rac1 or Rap1 rescued neurite outgrowth in Dock4-knockdown neurons; Rac1 restored mature spines, while Rap1 only promoted filopodia/thin spines.
Methods
- Constructs included human Dock4-WT, Dock4-945VS, Dock4-R853H, ΔSH3, ΔC, SH3-F, AAA mutant, and Dock4 shRNA, expressed in HEK293T, COS7, Neuro-2a cells, and primary E18 rat hippocampal neurons; Dock4 KO mice were also used.
- Rac1/Rap1 activity was measured by GST-PBD or GST-RalGDS pull-down and Western blot; morphology, neurite length, and spine density were assessed by immunocytochemistry and ImageJ; synaptic transmission was measured by whole-cell patch-clamp mEPSC recordings at 15 DIV.
- Data are means ± SEM; two-group comparisons used unpaired Student’s t-test, and three-or-more-group comparisons used one-way ANOVA, with significance at P < 0.05 (Prism 7.0).
Limitations
- The paper states that further studies are required to determine whether DHR2 directly activates Rap1 or acts via other Rap1-regulating proteins, and whether R853 maintains structural integrity or recruits critical regulators.
- Evident from the text: most functional data rely on exogenous expression in cell lines and cultured neurons or knockdown rescue, with no in vivo expression of the mutants and no behavioral readouts for the two variants.
- Evident from the text: the study does not directly demonstrate that these DOCK4 variants cause ASD or dyslexia phenotypes; it provides molecular and cellular evidence relevant to shared pathophysiology.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
15 of 30 cited sources checked · 9 supported · 1 flagged · accuracy not yet measured
- Premisecitation
Disruptions of neuronal migration and neurite outgrowth contribute importantly to the pathogenesis of dyslexia.
“The molecular pathophysiology of dyslexia is less understood, but lines of evidence suggest that disruptions of neuronal migration and neurite outgrowth contribute importantly to the pathogenesis of the disease (Poelmans et al., 2011; Shao et al., 2016; Guidi et al., 2018).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Poelmans et al., 2011 source
- cites Shao et al., 2016 source
- cites Guidi et al., 2018 source
The Introduction describes why neuronal migration and axon growth became proposed explanations for dyslexia, but says the evidence for the migration hypothesis is not very robust and the link should be treated with caution. The Conclusion and Future Directions says further studies are needed to establish how far migration abnormalities cause dyslexia. Thus, the review does not support the attributed suggestion that these disruptions contribute importantly to its pathogenesis. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
Dock4 is capable of activating Rap1.
“Interestingly, evidence from other system suggests that Dock4 is also capable of activating Rap1 (Yajnik et al., 2003), another small G protein involved in cell adhesion and growth.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Yajnik et al., 2003 source
- Premisecitation
Two specific DOCK4 variations, Exon27-52 deletion (Dock4-945VS) and rs2074130 missense (Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties.
“Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties.”
- Also stated in: § Introduction · plain
“Two DOCK4 variations have been identified in individuals with dyslexia and/or in autism subjects with poor reading abilities (Pagnamenta et al., 2010; Shao et al., 2016) (Table 1 and Figure 1A).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Pagnamenta et al., 2010 source
The Results (page unavailable) describe a DOCK4 deletion in an ASD family whose carriers had poor reading ability, and a second deletion that co-segregated with dyslexia. The Discussion cautions that larger studies are needed to confirm DOCK4’s relevance to reading ability. Our copy does not identify the deletion as Exon27–52 or its product as Dock4-945VS, and it does not report the rs2074130/Dock4-R853H missense variant. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Shao et al., 2016 source
- Also stated in: § Introduction · plain
- Premisecitation
The Exon27-52 deletion in DOCK4 causes a frameshift after amino acid 945, producing Dock4-945VS (1-945 aa + Val + Ser) with a premature stop.
“This variant leads to the deletion of the DHR2-containing C-terminal coding sequence of DOCK4 (Exons 27-52), which causes a frameshift of Dock4 protein coding after 945 aa; two missense amino acids, namely Valine (Val) and Serine (Ser), is translated after 945 aa, followed by a premature stop codon (Pagnamenta et al., 2010).”
- Also stated in: § Introduction · plain
“Frame shift after 945a.a., stop at 947a.a.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Pagnamenta et al., 2010 source
The Results (page unavailable) report an out-of-frame DOCK4–IMMP2L fusion transcript predicted to translate Valine–Serine followed by a premature stop codon. Our copy does not specify a frameshift after amino acid 945 or identify exons 27–52 as the deleted sequence, so those details are not verified by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Also stated in: § Introduction · plain
- Premisecitation
Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication.
“Our previous study using Dock4 knockout mice have revealed that Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication (Guo et al., 2019).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Guo et al., 2019 source
- Premisecitation
Impairment of Dock4-dependent excitatory synapse transmission in hippocampal CA1 pyramidal neurons is a main cause for the social deficits.
“In particular, impairment of Dock4-dependent excitatory synapse transmission in hippocampal CA1 pyramidal neurons is a main cause for the social deficits (Guo et al., 2019).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Guo et al., 2019 source
- Premisecitation
DOCK4 is one of few genes associated with both autism spectrum disorder (ASD) and dyslexia.
“DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.”
- Also stated in: § Introduction · plain
“Notably, DOCK4 is one of few shared candidate genes for both ASD and dyslexia.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Pagnamenta et al., 2010 source
The Results report DOCK4 deletions in an ASD family and a deletion co-segregating with dyslexia in another family. The Discussion cautions that larger studies are needed to confirm DOCK4’s relevance to reading ability; the paper also does not establish that it is one of only a few genes linked to both conditions. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites Shao et al., 2016 source
- Also stated in: § Introduction · plain
- Findingcitation
Knockdown of Dock4 resulted in dramatic decrease of spine density, especially the density of mushroom-shaped mature spines, in cultured hippocampal neurons.
“As reported before (Ueda et al., 2013), knockdown of Dock4 resulted in dramatic decrease of spine density, especially the density of the mushroom-shaped mature spines (Figures 7D,E).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Ueda et al., 2013 source
In Results, “Knockdown of Dock4 reduces dendritic spine density” (page unavailable), Dock4 knockdown significantly reduced spine density in cultured hippocampal neurons. The paper does not report that knockdown alone especially reduced mushroom-shaped mature spines; its Discussion (page unavailable) describes a decrease in those spines under the more specific condition of expressing a Dock4 mutant lacking the cortactin-binding region in knockdown neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Dock4 is important for neurite outgrowth and synapse morphogenesis during neuronal development.
“Previous evidence has revealed that Dock4 is important for neurite outgrowth and synapse morphogenesis during neuronal development (Ueda et al., 2008, 2013; Xiao et al., 2013).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
ASD may share etiologies of language and verbal communication deficits with dyslexia and LI.
“Nonetheless, both diseases are well-documented comorbid diseases of language impairment (LI) with similar language traits, suggesting that ASD may share etiologies of language and verbal communication deficits with dyslexia and LI (Eicher and Gruen, 2015).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Eicher and Gruen, 2015 source
- Premisecitation
Deficiency of Dock4 in vivo leads to social and communication deficits.
“Using Dock4 knockout mice, we have shown that deficiency of Dock4 in vivo leads to social and communication deficits (Guo et al., 2019).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Guo et al., 2019 source
- Findingown data
Much weaker F-actin staining was observed in R853H- or 945VS-expressed cells.
“In contrast, much weaker F-actin staining was observed in R853H- or 945VS-expressed cells (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
Rap1 activation is significantly compromised in Dock4 knockout mouse hippocampus.
“We showed here that Rap1 activation was significantly compromised in Dock4 KO hippocampus (Figures 2C,D), suggesting that Dock4 is capable of activating Rap1 in nervous system.”
Quote in the paperSubstantial claim - Findingown data
Strong F-actin staining was observed in the cytoplasm and at the membrane of cells expressing Dock4-WT.
“Interestingly, strong staining of F-actin was observed in the cytoplasm and at the membrane of cells expressed with Dock4-WT (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
The SH3-lacking Dock4 (ΔSH3) could not activate Rap1.
“Similarly, we observed that the SH3-lacking Dock4 (ΔSH3) could not activate Rap1, whereas the C-terminus-lacking Dock4 (ΔC) had intact Rap1-activation ability (Figures 3A–C).”
Quote in the paperSubstantial claim - Findingown data
HEK293T cells overexpressed with Dock4-WT exhibited a spread, elongated morphology with enlargement of both cytosolic and nuclear regions compared to vector-expressed cells.
“Indeed, HEK293T cells overexpressed with Dock4-WT exhibited a spread, elongated morphology with enlargement of both cytosolic and nuclear regions when compared to the vector-expressed cells (Figures 4A–C).”
Quote in the paperSubstantial claim - Findingown data
The cellular location of Dock4-R853H and Dock4-945VS was mainly enriched in the cytoplasm, similar to Dock4-WT.
“The cellular location of Dock4-R853H and 945VS was mainly enriched in the cytoplasm, which was similar to that of Dock4-WT (Figure 4A).”
Quote in the paperNot a substantial claim - Findingown data
When SH3-F was added to the Dock4-FL and ELMO2 complex, Rap1 activation was completely abolished.
“Consistently, when SH3-F was added to the Dock4-FL and ELMO2 complex, the Rap1 activation was completely abolished (Figures 3D,E).”
Quote in the paperSubstantial claim - Findingown data
ELMO2, without altering Rap1 levels by itself, appeared to further substantiate the effect of Dock4-FL on Rap1 activation.
“Notably, ELMO2, without altering Rap1 levels by itself, appeared to further substantiate the effect of Dock4-FL on Rap1 activation (Figures 3D,E).”
Quote in the paperSubstantial claim - Findingown data
Dock4-R853H and Dock4-945VS failed to influence overall cell morphology, as cellular size was not changed by either mutant.
“However, Dock4-R853H and 945VS failed to influence the overall cell morphology, as the cellular size was not changed by either mutant (Figures 4A–C).”
Quote in the paperSubstantial claim - Findingown data
The C-terminus-lacking Dock4 (ΔC) had intact Rap1-activation ability.
“Similarly, we observed that the SH3-lacking Dock4 (ΔSH3) could not activate Rap1, whereas the C-terminus-lacking Dock4 (ΔC) had intact Rap1-activation ability (Figures 3A–C).”
Quote in the paperSubstantial claim - Findingown data
ELMO2 did not have any effect on Rap1 in Dock4-ΔSH3-expressing cells.
“In contrast, ELMO2 did not have any effect on Rap1 in Dock4-ΔSH3-expressing cells (Figures 3D,E).”
Quote in the paperSubstantial claim - Findingcitation
Dock4-945VS totally lost the ability to activate Rac1.
“As previously reported (Xiao et al., 2013), 945VS totally lost the Rac1-activation ability (Figures 2A,B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xiao et al., 2013 source
- Findingown data
Arg853 and its flanking sequences are highly conserved during evolution.
“By using the Multiple Sequence Alignment analysis tool of Clustal Omega2, we found that the Arg853 and its flanking sequences are highly conserved during evolution (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
The region around Arg853 is not conserved in other Dock family members.
“However, this region is not conserved in other Dock family members (Figure 1C), suggesting that this region is unique in Dock4.”
Quote in the paperNot a substantial claim - Findingown data
Arg853 of human Dock4 is located in the linker region between DHR1 and DHR2 domains.
“Arg853 of human Dock4 is located in the linker region between DHR1 and DHR2 domains (Figure 1A), a region that has no known molecular function yet.”
Quote in the paperNot a substantial claim - Findingown data
Dock4 mainly promoted the mushroom-shaped spine (mature spines) in cultured hippocampal neurons.
“By quantifying different types of spines, we found that Dock4 mainly promoted the mushroom-shaped spine, which is believed as the mature spines, whereas both mutants lacked this ability (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
Both Dock4 mutants had compromised function in promoting neurite outgrowth and dendritic spine formation.
“Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation.”
Quote in the paperSubstantial claim - Findingown data
Rap1 is another small GTPase besides Rac1 that can be activated by Dock4 in brain.
“The current study further confirms that Rap1 is another small GTPase besides Rac1 that can be activated by Dock4 in brain.”
Quote in the paperSubstantial claim - Findingown data
Both Dock4-R853H and Dock4-945VS lacked the ability to promote mushroom-shaped spines.
“By quantifying different types of spines, we found that Dock4 mainly promoted the mushroom-shaped spine, which is believed as the mature spines, whereas both mutants lacked this ability (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
Dock4-R853H and Dock4-945VS fail to influence cell morphology.
“Dock4-R853H and 945VS fail to influence cell morphology.”
Quote in the paperNot a substantial claim - Findingown data
Dock4 shRNA significantly decreased neurite length in cultured hippocampal neurons.
“Whereas Dock4 shRNA decreased neurite length significantly, co-expression of either Rac1 or Rap1 was able to rescue this impaired neurite outgrowth (Figures 7B,C).”
Quote in the paperSubstantial claim - Findingown data
Dock4-945VS completely lost the ability to promote mEPSC.
“By contrast, Dock4-945VS completely lost the ability to promote mEPSC (Figures 6C–E).”
Quote in the paperSubstantial claim - Findingown data
R853H also showed moderate decrease in RacGEF activity.
“Interestingly, R853H also showed moderate decrease in RacGEF activity.”
Quote in the paperSubstantial claim - Findingown data
The RacGEF activities of both Dock4-R853H and Dock4-945VS are compromised.
“In the initial biochemical assays, we found that the RacGEF activities of both mutants are compromised.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Rac1 specifically restored the density of mature spines in Dock4-knockdown neurons.
“Importantly, overexpression of Rac1 specifically restored the density of these mature spines in Dock4-knockdown neurons (Figures 7D,E).”
Quote in the paperSubstantial claim - Findingown data
Dock4 substantially promoted neurite elongation in Neuro-2a cells upon retinoic acid (RA) stimulation.
“When transfected into Neuro-2a cells, Dock4 substantially promoted neurite elongation upon retinoic acid (RA) stimulation (Figures 5A–C).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Rap1 could not reverse the decrease of mature spines in Dock4-knockdown neurons.
“Overexpression of Rap1, on the other hand, only promoted growth of filopodia/thin type of spines which are believed as the dynamic immature spines, but could not reverse the decrease of mature spines in Dock4-knockdown neurons (Figures 7D,E).”
Quote in the paperSubstantial claim - Findingown data
Both Dock4-R853H and Dock4-945VS lost the ability to promote axon or total neurite elongation in cultured hippocampal neurons compared to WT protein.
“As observed in Neuro-2a cells, both mutants lost the ability to promote axon or total neurite elongation when compared to the WT protein (Figures 5D–F).”
- Also stated in: § Dock4-R853H and 945VS Lack Neurite Outgrowth Abilities · plain
“Dock4 mutants could not promote neurite outgrowth in hippocampal neurons.”
Quote in the paperSubstantial claim - Also stated in: § Dock4-R853H and 945VS Lack Neurite Outgrowth Abilities · plain
- Findingown data
Dock4-R853H and Dock4-945VS disrupt actin cytoskeleton in COS7 cells.
“Dock4 R853H and 945VS disrupt actin cytoskeleton in COS7 cells.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Rap1 promoted growth of filopodia/thin type of spines (dynamic immature spines) in Dock4-knockdown neurons.
“Overexpression of Rap1, on the other hand, only promoted growth of filopodia/thin type of spines which are believed as the dynamic immature spines, but could not reverse the decrease of mature spines in Dock4-knockdown neurons (Figures 7D,E).”
Quote in the paperSubstantial claim - Findingown data
Co-expression of either Rac1 or Rap1 rescued the impaired neurite outgrowth in Dock4-knockdown hippocampal neurons.
“Whereas Dock4 shRNA decreased neurite length significantly, co-expression of either Rac1 or Rap1 was able to rescue this impaired neurite outgrowth (Figures 7B,C).”
- Also stated in: § Rac1 and Rap1 Rescue the Defects of Neurite Outgrowth and Spine Morphogenesis in Dock4 Knockdown Neurons · plain
“Rac1 and Rap1 rescue neurite outgrowth defects in Dock4-knockdown hippocampal neurons.”
Quote in the paperSubstantial claim - Also stated in: § Rac1 and Rap1 Rescue the Defects of Neurite Outgrowth and Spine Morphogenesis in Dock4 Knockdown Neurons · plain
- Findingown data
Dock4-945VS completely fails to regulate synaptic transmission.
“Dock4-945VS, on the other hand, completely fails to regulate synaptic transmission.”
Quote in the paperSubstantial claim - Findingown data
Both Dock4-945VS and R853H totally lost the ability to activate Rap1.
“Both Dock4-945VS and R853H totally lost the ability to activate Rap1.”
Quote in the paperSubstantial claim - Findingown data
Neither Dock4-R853H nor Dock4-945VS was able to influence neurite outgrowth in Neuro-2a cells, with neurite length comparable to vector-expressed cells.
“However, neither Dock4-R853H nor Dock4-945VS was able to influence neurite outgrowth, as the neurite length of cells expressed with either mutant was comparable to that of the vector-expressed cells (Figures 5A–C).”
- Also stated in: § Dock4-R853H and 945VS Lack Neurite Outgrowth Abilities · plain
“Dock4 mutants could not promote RA-induced neurite outgrowth in Neuro-2a cells.”
Quote in the paperSubstantial claim - Also stated in: § Dock4-R853H and 945VS Lack Neurite Outgrowth Abilities · plain
- Findingown data
Dock4-WT expression remarkably increased spine density in cultured hippocampal neurons compared to vector-expressed neurons.
“As reported before, we observed a remarkable increase of spine density in Dock4-WT expressed neurons as compared to vector expressed neurons (Figures 6A,B).”
Quote in the paperSubstantial claim - Findingown data
Neither Dock4-R853H nor Dock4-945VS was able to influence spine density in cultured hippocampal neurons.
“However, neither R853H nor 945VS was able to influence spine density (Figures 6A,B).”
- Also stated in: § Dock4-R853H and 945VS Have Compromised Abilities to Promote Dendritic Spine Morphogenesis and Synaptic Transmission · plain
“Dock4 mutants could not promote dendritic spine formation in hippocampal neurons.”
Quote in the paperSubstantial claim - Also stated in: § Dock4-R853H and 945VS Have Compromised Abilities to Promote Dendritic Spine Morphogenesis and Synaptic Transmission · plain
- Findingown data
Dock4-R853H is still able to promote excitatory synaptic transmission, although this ability is weaker than the WT protein.
“By using electrophysiological approaches, we further demonstrate that Dock4-R853H is still able to promote excitatory synaptic transmission, although this ability is weaker than the WT protein.”
Quote in the paperSubstantial claim - Findingown data
The effect of Rac1 on rescuing neurite outgrowth appeared stronger than that of Rap1.
“Notably, the effect of Rac1 appeared to be stronger than Rap1 (Figures 7B,C).”
Quote in the paperNot a substantial claim - Findingown data
Dock4-WT increased both amplitude and frequency of mEPSC in cultured hippocampal neurons compared to vector.
“Consistently, Dock4-WT increased both amplitude and frequency of mEPSC, suggesting that there were more functional excitatory synapses in Dock4 WT expressed neurons than in vector expressed neurons (Figures 6C–E).”
Quote in the paperSubstantial claim - Interpretationown data
Dock4 is capable of activating Rap1 in the nervous system.
“We showed here that Rap1 activation was significantly compromised in Dock4 KO hippocampus (Figures 2C,D), suggesting that Dock4 is capable of activating Rap1 in nervous system.”
Quote in the paperSubstantial claim - Premisecitation
The rs20741307 variation causes a missense mutation substituting Arginine at residue 853 with Histidine (Dock4-R853H).
“p.R853H”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shao et al., 2016 source
- Premisecitation
Rac1 is a key molecule that mediates Dock4's function.
“Indeed, Rac1 was demonstrated to be a key molecule that mediates Dock4’s function in the above studies.”
Quote in the paperSubstantial claim - Interpretationown data
ELMO2, through forming a complex with Dock4, promotes the function of Dock4's DHR2 domain on both Rac1 and Rap1 activation.
“These results suggest that ELMO2, through forming a complex with Dock4, promotes the function of Dock4’s DHR2 domain on both Rac1 and Rap1 activation.”
Quote in the paperSubstantial claim - Interpretationown data
The two autism/dyslexia-linked mutants of Dock4 showed impaired abilities on activation of both Rac1 and Rap1.
“Hence, the two autism/dyslexia-linked mutants of Dock4 showed impaired abilities on activation of both Rac1 and Rap1.”
- Also stated in: § Abstract · plain
“Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Premisecitation
The protein product of the IMMP2L_DOCK4 fusion transcript is unable to exert normal function on Rac1 activation and neurite outgrowth.
“Previously, we showed that the protein product of the IMMP2L_DOCK4 fusion transcript is unable to exert normal function on Rac1 activation and neurite outgrowth (Xiao et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xiao et al., 2013 source
- Interpretationown data
The region around Arg853 is unique in Dock4 among Dock family members.
“However, this region is not conserved in other Dock family members (Figure 1C), suggesting that this region is unique in Dock4.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The DHR2 domain is responsible for not only Rac1, but also Rap1 activation by Dock4.
“As 945VS, which lacks both DHR2 and the C-terminus, lost the Rap1-activating ability, it suggests that the DHR2 is responsible for not only Rac1, but also Rap1 activation.”
Quote in the paperSubstantial claim - Interpretationown data
Rac1 and Rap1 may corporately participate in Dock4-mediated neurite outgrowth.
“Together, the rescue experiments at different neuronal developmental stages suggest that Rac1 and Rap1 may corporately participate in Dock4-mediated neurite outgrowth, and Rac1 is specifically required for Dock4-mediated formation of mature spines.”
Quote in the paperSubstantial claim - Interpretationreasoning
The RacGEF catalytic activity of DHR2 is not necessary for Rap1 activation.
“However, the RacGEF catalytic activity of DHR2 is not necessary for Rap1 activation, suggesting Dock4 uses different mechanism to activate Rac1 and Rap1 respectively.”
Quote in the paperSubstantial claim - Interpretationown data
The findings provide insights into the common molecular pathophysiology of ASD and dyslexia.
“Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.”
- Also stated in: § Introduction · plain
“This study provides insights in understanding the common molecular pathophysiology of autism and dyslexia by investigating their shared gene DOCK4.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Interpretationown data
R853 is a previously uncharacterized site for the regulation of the integrity of Dock4 function.
“Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.”
Quote in the paperSubstantial claim - Interpretationreasoning
The loss of RacGEF activity is expected for Dock4-945VS because this mutant lacks the entire GEF domain (DHR2 domain).
“The loss of RacGEF activity is expected for Dock4-945VS because this mutant lacks the entire GEF domain, i.e., DHR2 domain.”
Quote in the paperSubstantial claim - Interpretationown data
Rac1 is mainly required for the formation of mature spines regulated by Dock4.
“Indeed, we showed that Rac1 is mainly required for the formation of mature spines regulated by Dock4, suggesting that Rac1 may be the primary small GTPases downstream of Dock4 for functional synapse formation and transmission.”
Quote in the paperSubstantial claim - Interpretationreasoning
Dock4-dependent regulation of neuronal development may underlie the neurobiology basis of social communication and language development.
“Findings of the current study provide further molecular and cellular evidence that Dock4-dependent regulation of neuronal development may underlie the neurobiology basis of social communication and language development.”
Quote in the paperSubstantial claim - Interpretationown data
Rac1 is specifically required for Dock4-mediated formation of mature spines.
“Together, the rescue experiments at different neuronal developmental stages suggest that Rac1 and Rap1 may corporately participate in Dock4-mediated neurite outgrowth, and Rac1 is specifically required for Dock4-mediated formation of mature spines.”
Quote in the paperSubstantial claim - Interpretationown data
Dock4-R853H and Dock4-945VS are dysfunctional in regulating cell morphology and cytoskeleton properly.
“Therefore, Dock4-R853H and 945VS are dysfunctional to regulate cell morphology and cytoskeleton properly.”
- Also stated in: § Abstract · plain
“Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationreasoning
Dock4 uses different mechanisms to activate Rac1 and Rap1.
“However, the RacGEF catalytic activity of DHR2 is not necessary for Rap1 activation, suggesting Dock4 uses different mechanism to activate Rac1 and Rap1 respectively.”
Quote in the paperSubstantial claim - Interpretationreasoning
R853 is probably a critical residue for the regulation of the DHR2 domain function.
“Nonetheless, these studies suggest that R853 is probably a critical residue for the regulation of the DHR2 domain function.”
Quote in the paperSubstantial claim - Interpretationown data
There were more functional excitatory synapses in Dock4-WT expressed neurons than in vector-expressed neurons.
“Consistently, Dock4-WT increased both amplitude and frequency of mEPSC, suggesting that there were more functional excitatory synapses in Dock4 WT expressed neurons than in vector expressed neurons (Figures 6C–E).”
Quote in the paperSubstantial claim - Interpretationown data
Rac1 may be the primary small GTPase downstream of Dock4 for functional synapse formation and transmission.
“Indeed, we showed that Rac1 is mainly required for the formation of mature spines regulated by Dock4, suggesting that Rac1 may be the primary small GTPases downstream of Dock4 for functional synapse formation and transmission.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 6
- May combine two claims. 14
Classified as probably not a substantial claim.
PremisecitationBoth ASD and dyslexia have strong genetic components in their etiologies that involve multigene interaction.
“Emerging evidence has suggested that both ASD and dyslexia have strong genetic components in their etiologies that involve multigene interaction (Raskind et al., 2012; Bourgeron, 2015).”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationDock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus.
“Previous studies in both Dock4 KO mice and in Dock4-shRNA knockdown neurons have shown that Dock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus (Ueda et al., 2013; Guo et al., 2019).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Ueda et al., 2013 source
The Results section, “Knockdown of Dock4 reduces dendritic spine density” (page unavailable), reports that Dock4 shRNA reduced spine density in cultured rat hippocampal neurons, supporting the spine-formation claim. The passages from our copy do not establish that this study tested Dock4 knockout mice or measured excitatory synaptic transmission. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Guo et al., 2019 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRac1 and Rap1 are important for spine enlargement and dynamics, respectively.
“These observations are consistent with the current knowledge on Rac1 and Rap1, which are important for spine enlargement and dynamics, respectively (Woolfrey and Srivastava, 2016).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Woolfrey and Srivastava, 2016 source
May combine two claims.
Findingown dataDock4-R853H decreased activated-Rac1 levels compared to wild-type Dock4, though the reduction was less robust than that caused by Dock4-945VS.
“R853H also decreased activated-Rac1 levels when compared to WT, although the reduction was not as robust as that caused by 945VS (Figures 2A,B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDock4-WT remarkably increased activated-Rap1 levels, whereas both Dock4-945VS and Dock4-R853H lacked this ability.
“Notably, while Dock4-WT remarkably increased activated-Rap1 levels, both mutants lacked this ability (Figures 2E,F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe RacGEF-dead Dock4-AAA mutant lost the ability to activate Rac1, but its Rap1-activating ability was unaltered.
“Interestingly, the AAA mutant did lose the ability to activate Rac1, but its Rap1-activating ability was unaltered (Figures 3F,G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDock4-R853H also increased mEPSC amplitude and frequency, but the effect was significantly weaker than that of Dock4-WT.
“Interestingly, Dock4-R853H also increased mEPSC amplitude and frequency, but the effect was significantly weaker than that of Dock4-WT (Figures 6C–E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataR853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability.
“Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe Rap1-activating function seems unique for Dock4 among Dock family members.
“This Rap1-activating function seems to be unique for Dock4, which has been the only Dock reported to possess this ability.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Premisenone givenDock4 possesses an N-terminal SH3 domain, a DHR1 domain, and a DHR2 domain, with DHR2 well-studied as a Rac1-specific GEF domain.
“Dock4 possesses an N-terminal SH3 (Src-homology 3) domain, a DHR1 (Dock homology region 1) domain, and a DHR2 domain which is well-studied as a Rac1-specific GEF domain.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenASD and dyslexia share similar communication deficits originating from impairments of reading or language.
“It has been found that ASD and dyslexia share similar communication deficits originated from impairments of reading or language.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDock4 does not activate Rap1 the same way as it activates Rac1, and alternate mechanisms besides RacGEF activity may underlie the requirement of DHR2 domain for Rap1 activation.
“Therefore, Dock4 does not activate Rap1 the same way as it activates Rac1, and alternate mechanisms besides RacGEF activity may underlie the requirement of DHR2 domain for Rap1 activation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDock4 is important for neuronal development and social behaviors.
“Dock4 is important for neuronal development and social behaviors.”
- Also stated in: § Introduction · hedged
“Dock4 is suggested to play important roles in neuronal development such as axon guidance, dendrite development and dendritic spine morphogenesis (Ueda et al., 2008, 2013; Xiao et al., 2013; Makihara et al., 2018).”
Quote in the paperSubstantial claim0 of 3 sources checked- Also stated in: § Introduction · hedged
May combine two claims.
InterpretationreasoningThe difference between Dock4-R853H and Dock4-945VS in synaptic transmission could be due to Dock4-R853 retaining some level of Rac1-activating ability, whereas 945VS lost both Rac1- and Rap1-activating abilities.
“This difference could be due to the fact that Dock4-R853 still retains some level of Rac1-activating ability, whereas 945VS lost both Rac1- and Rap1-activating abilities.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationASD is a disease with impaired neuronal connectivity.
“Despite heterogeneous origins, emerging genetic and pathological findings point to a conclusion that ASD is a disease with impaired neuronal connectivity (Bourgeron, 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bourgeron, 2015 source
May combine two claims.
Interpretationown dataDock4-R853H retains partial function, whereas Dock4-945VS loses the whole function on regulating excitatory synaptic transmission.
“Together, these findings suggest that Dock4-R853H retains partial function, whereas 945VS loses the whole function on regulating excitatory synaptic transmission.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningFindings in this study are consistent with the neurodevelopment impairment hypothesis of ASD and dyslexia, in which DOCK4 contributes to a shared genetic factor for both disorders.
“Findings in this study are consistent with the neurodevelopment impairment hypothesis of ASD and dyslexia, in which DOCK4 contributes to a shared genetic factor for both disorders.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationDHR2 domain as well as binding to ELMO2 via SH3 domain are necessary for Rap1 activation.
“Domain mapping analysis suggests that similar to Rac1 activation (Xiao et al., 2013), DHR2 domain as well as binding to ELMO2 via SH3 domain are necessary for Rap1 activation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xiao et al., 2013 source
The paper relies on this without support.
Whether Dock4 regulates Rap1 in the nervous system had not been studied before this study.
“However, whether Dock4 regulates Rap1 in the nervous system has not been studied.”
The paper relies on this without support.
Whether the rs20741307 variation affects Dock4's Rac1 activation and neurite outgrowth abilities had not been explored before this study.
“However, whether rs20741307 variation affects these Dock4 abilities has not been explored.”
The paper relies on this without support.
Whether the two DOCK4 variations influence the synaptic regulation function of Dock4 was unclear before this study.
“Moreover, whether these two variations influence the synaptic regulation function of Dock4 is unclear.”
The paper relies on this without support.
Rac1 and Rap1 regulate cell morphology by influencing cytoskeleton and cell adhesion.
“We have shown that Dock4-R853H and 945VS exhibit decreased activities toward both Rac1 and Rap1, which regulate cell morphology by influencing cytoskeleton and cell adhesion.”
The paper relies on this without support.
Very few shared risk genes have been identified in both ASD and dyslexia.
“So far, very few shared risk genes have been identified in both ASD and dyslexia.”
The paper relies on this without support.
The molecular function of Dock4-R853H is uncharacterized before.
“Among them, the molecular function of Dock4-R853H is uncharacterized before.”
The paper relies on this without support.
R853 and its flanking regions are unique sequence in Dock4 among Dock family members.
“R853 and its flanking regions are unique sequence in Dock4 among Dock family members, it may represent a special site of regulation only in Dock4 but not in other Docks.”
The paper relies on this without support.
The two DOCK4 variants (Exon27-52 deletion and rs2074130) are associated with dyslexia and/or ASD with reading difficulties.
“The current study focuses on two DOCK4 variants, Exon27-52 deletion (protein product: Dock4-945VS and rs2074130 variation (protein product: Dock4-R853H), which are associated with dyslexia and/or ASD with reading difficulties.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DOCK4 variants leading to reduced GEF activity and subsequent deficits in neuronal morphology have been linked to neuropsychiatric disorders such as autism, dyslexia, and schizophrenia.
“DOCK4 variants leading to reduced GEF activity and subsequent deficits in neuronal morphology have been linked to neuropsychiatric disorders such as autism, dyslexia, and schizophrenia (84, 85).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [85]
The Abstract reports that two variants associated with autism and/or dyslexia have reduced ability to activate Rac1 and Rap1 and impaired neurite outgrowth and spine formation. The Introduction also lists schizophrenia among conditions linked to DOCK4, but the paper does not link the tested variants or their measured neuronal effects specifically to schizophrenia. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLoss of DOCK4 function is compensated by overexpression of the DOCK4 interacting partner RAC1, as demonstrated in vitro and in vivo.
“loss of DOCK4 function is compensated by overexpression of the DOCK4 interacting partner RAC1, as demonstrated in vitro (Huang et al. 2019) and in vivo (Guo et al. 2021)”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Huang et al. 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 2E lists R853H twice instead of the two mutants
MinorThe Figure 2E caption says R853H was expressed twice and does not list 945VS, although the results describe that assay as comparing both mutants' Rap1 activation.
“Dock4-R853H, Dock4-R853H or Dock4-WT were expressed in HEK293T cells, and the levels of Rap1-GTP were analyzed.”
“Notably, while Dock4-WT remarkably increased activated-Rap1 levels, both mutants lacked this ability (Figures 2E,F).”
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“Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et…”
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“Despite heterogeneous origins, emerging genetic and pathological findings point to a conclusion that ASD is a disease with impaired neuronal connectivity (Bourgeron, 2015).”
BackgroundRates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
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“Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et…”
BackgroundDOCK4, a GTPase activator, is disrupted during tumorigenesis.
Yajnik, V., Paulding, C., Sordella, R., McClatchey, A. I., Saito, M., Wahrer, D. C. R., Reynolds, P., Bell, D. W., Lake, R., van den Heuvel, S., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00155-7 · Cited by 230 · see citing works
Recognizing Psychiatric Comorbidity With Reading Disorders
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“Indeed, difficulties of reading comprehension is a common symptoms in ASD children (prevalence ranging from 6 to 30%) (Hendren et al., 2018).”
BackgroundInsights into the biological functions of Dock family guanine nucleotide exchange factors
Laurin, M., & Côté, J.-F. (2014) · Genes & Development · doi:10.1101/gad.236349.113 · Cited by 160 · see citing works
IMGSAC, Maestrini, E., Pagnamenta, A. T., Lamb, J. A., Bacchelli, E., Sykes, N. H., Sousa, I., Toma, C., Barnby, G., Butler, H., et al. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.34 · Cited by 143 · cited 1× · see citing works
“Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et…”
BackgroundPagnamenta, A. T., Bacchelli, E., de Jonge, M. V., Mirza, G., Scerri, T. S., Minopoli, F., Chiocchetti, A., Ludwig, K. U., Hoffmann, P., Paracchini, S., et al. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.02.002 · Cited by 139 · cited 4× · see citing works
“The first variation, identified in individuals from a European family with autism and/or reading/spelling difficulties, is a microdeletion at the junction of DOCK4 and its neighboring gene IMMP2L (deletion at chr7:110663978-111257682, GRCh37) (Pagnamenta et al., 2010).”
BackgroundInfluentialA theoretical molecular network for dyslexia: integrating available genetic findings.
Poelmans, G., Buitelaar, J. K., Pauls, D. L., & Franke, B. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.105 · Cited by 119 · cited 1× · see citing works
“Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et…”
BackgroundToma, C., Torrico, B., Hervás, A., Valdés-Mas, R., Tristán-Noguero, A., Padillo, V, Maristany, M., Salgado, M., Arenas, C., Puente, X. S., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.106 · Cited by 114 · see citing works
α2-Chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse
Shi, L., Fu, W., Hung, K.-W., Porchetta, C., Hall, C., Fu, A. K. Y., & Ip, N. Y. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706626104 · Cited by 109 · cited 1× · see citing works
“Rac1/Rap1 activity was measured as previously described (Shi et al., 2007; Bai et al., 2018).”
MethodSelf-citationGuo, D., Peng, Y., Wang, L., Sun, X., Wang, X., Liang, C., Yang, X., Li, S., Xu, J., Ye, W.-C., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-019-0472-7 · Cited by 102 · cited 5× · see citing works
“Our previous study using Dock4 knockout mice have revealed that Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication (Guo et al., 2019).”
BackgroundMethodInfluentialSelf-citationα2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2
Ip, J. P. K., Shi, L., Chen, Y., Itoh, Y., Fu, W., Betz, A., Yung, W., Gotoh, Y., Fu, A. K. Y., & Ip, N. Y. (2011) · Nature Neuroscience · doi:10.1038/nn.2972 · Cited by 84 · cited 1× · see citing works
“All cDNAs with a C-terminal Flag tag were subcloned into the pCAGIG vector, which contains a GFP coding sequence separated by an internal ribosome entry site (Ip et al., 2012).”
MethodSelf-citationDock protein family in brain development and neurological disease
Shi, L. (2013) · Communicative & Integrative Biology · doi:10.4161/cib.26839 · Cited by 83 · cited 1× · see citing works
“Dock (dedicator of cytokinesis) protein family, a subtype of atypical guanine nucleotide exchange factors (GEFs) for promoting the activity of Rac1/Cdc42, has been implicated in regulating various processes of brain development and is linked with neurological diseases (Shi, 2013).”
BackgroundSelf-citationControl of dendritic spine morphological and functional plasticity by small GTPases.
Woolfrey, K. M., & Srivastava, D. P. (2016) · Neural Plasticity · doi:10.1155/2016/3025948 · Cited by 76 · see citing works
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Self-citationThe genetics of reading disabilities: from phenotypes to candidate genes.
Raskind, W. H., Peter, B., Richards, T., Eckert, M. M., & Berninger, V. W. (2013) · Frontiers in Psychology · doi:10.3389/fpsyg.2012.00601 · Cited by 71 · see citing works
Dock4 regulates dendritic development in hippocampal neurons.
Ueda, S., Fujimoto, S., Hiramoto, K., Negishi, M., & Katoh, H. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21763 · Cited by 61 · cited 2× · see citing works
“Moreover, Dock4 is suggested to play important roles in neuronal development such as axon guidance, dendrite development and dendritic spine morphogenesis (Ueda et al., 2008, 2013; Xiao et al., 2013; Makihara et al., 2018).”
BackgroundThe neuronal migration hypothesis of dyslexia: a critical evaluation 30 years on.
Guidi, L. G., Velayos‐Baeza, A., Martinez‐Garay, I., Monaco, A. P., Paracchini, S., Bishop, D. V. M., & Molnár, Z. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14149 · Cited by 59 · cited 1× · see citing works
“The molecular pathophysiology of dyslexia is less understood, but lines of evidence suggest that disruptions of neuronal migration and neurite outgrowth contribute importantly to the pathogenesis of the disease (Poelmans et al., 2011; Shao et al., 2016; Guidi et al., 2018).”
BackgroundDOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population
Alkelai, A., Lupoli, S., Greenbaum, L., Kohn, Y., Kanyas, K., Ben‐Asher, E., Lancet, D., Macciardi, F. M., & Lerer, B. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000903 · Cited by 57 · see citing works
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Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation.
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“As reported before (Ueda et al., 2013), knockdown of Dock4 resulted in dramatic decrease of spine density, especially the density of the mushroom-shaped mature spines (Figures 7D,E).”
BackgroundInfluentialTang, G., Dong, X., Huang, X., Huang, X., Liu, H., Wang, Y., Ye, W., & Shi, L. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.019 · Cited by 46 · cited 1× · see citing works
“Primary cultures of rat hippocampal neurons were prepared from E18 Sprague Dawley rat embryos as described previously (Xiao et al., 2013; Tang et al., 2015).”
MethodSelf-citationShao, S., Kong, R., Zou, L., Zhong, R., Lou, J., Zhou, J., Guo, S., Wang, J., Zhang, X., Zhang, J., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9334-8 · Cited by 44 · see citing works
Self-citationPolarized Dock Activity Drives Shh-Mediated Axon Guidance.
Makihara, S., Morin, S., Ferent, J., Côté, J.-F., Yam, P. T., & Charron, F. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.07.007 · Cited by 37 · cited 1× · see citing works
“Moreover, Dock4 is suggested to play important roles in neuronal development such as axon guidance, dendrite development and dendritic spine morphogenesis (Ueda et al., 2008, 2013; Xiao et al., 2013; Makihara et al., 2018).”
BackgroundLiang, S., Wang, X.-L., Zou, M.-Y., Wang, H., Zhou, X., Sun, C.-H., Xia, W., Wu, L.-J., Fujisawa, T. X., & Tomoda, A. (2014) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b1300133 · Cited by 33 · cited 1× · see citing works
“Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et…”
BackgroundZhang, J., Yin, Y., Ji, Z., Cai, Z., Zhao, B., Li, J., Tan, M., & Guo, G. (2017) · Neural Plasticity · doi:10.1155/2017/8197085 · Cited by 29 · cited 13× · see citing works
“Second, transfection of Dock4 shRNA together with either Rac1 or Rap1 was performed at 9 DIV, and spine morphology was examined at 16 DIV (Figure 7D).”
MethodInfluentialSelf-citationLiao, Y., Zhuang, X., Huang, X., Peng, Y., Ma, X., Huang, Z.-X., Liu, F., Xu, J., Wang, Y., Chen, W., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00290 · Cited by 20 · see citing works
Self-citationBai, Y., Guo, D., Sun, X., Tang, G., Liao, T., Peng, Y., Xu, J., & Shi, L. (2018) · Journal of Cell Science · doi:10.1242/jcs.215251 · Cited by 18 · cited 1× · see citing works
“Rac1/Rap1 activity was measured as previously described (Shi et al., 2007; Bai et al., 2018).”
MethodSelf-citationA Pooled Genome-Wide Association Study of Asperger Syndrome
Warrier, V., Chakrabarti, B., Murphy, L., Chan, A., Craig, I., Mallya, U., Lakatošová, S., Rehnstrom, K., Peltonen, L., Wheelwright, S., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0131202 · Cited by 11 · see citing works
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“…dyslexia and schizophrenia (Maestrini et al., 2010; Pagnamenta et al., 2010; Poelmans et al., 2011; Alkelai et al., 2012; Iossifov et al., 2014; Liang et al., 2014; Toma et al., 2014; Warrier et al., 2015; Shao et al., 2016; Lim et al., 2017; Akahoshi and Yamamoto, 2018; Kushima et al., 2018).”
Flagged first, then by citations
Cited by
Sorted by citations
Guo, D., Yang, X., & Shi, L. (2020) · Cells · doi:10.3390/cells9040835 · Cited by 73 · see citing works
Self-citationScala, M., Nishikawa, M., Nagata, K., & Striano, P. (2021) · Cells · doi:10.3390/cells10123395 · Cited by 43 · see citing works
Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses
Duman, J. G., Blanco, F. A., Cronkite, C. A., Ru, Q., Erikson, K., Mulherkar, S. A., Saifullah, A. B., Firozi, K., & Tolias, K. F. (2021) · Small GTPases · doi:10.1080/21541248.2021.1885264 · Cited by 33 · see citing works
“strongly overlap in the forebrain [114,115] and DOCK4 functions in dendrite and spine development [115,116].”
BackgroundBiological implications of genetic variations in autism spectrum disorders from genomics studies
Zhang, Y., Liu, X., Guo, R., Xu, W., Guo, Q. J., Hao, C., Ni, X., & Li, W. (2021) · Bioscience Reports · doi:10.1042/bsr20210593 · Cited by 29 · see citing works
DOCK4 stimulates MUC2 production through its effect on goblet cell differentiation
Qin, T., Yang, J., Huang, D., Zhang, Z., Huang, Y., Chen, H., & Xu, G. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30325 · Cited by 25 · see citing works
“…mammals, named DOCK1 to DOCK11 that play different cellular functions such as cardiovascular differentiation, axon outgrowth, leukocyte migration, cancer cell invasion, neurite outgrow, and synapse development (Gadea & Blangy, 2014; Huang et al., 2020; Laurin & Cote, 2014; Namekata et al., 2014).”
BackgroundNeural circuit mechanisms that govern inter-male attack in mice
Zha, X., & Xu, X. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03956-x · Cited by 24 · see citing works
The Potential Role of AMPA Receptor Trafficking in Autism and Other Neurodevelopmental Conditions
Niescier, R. F., & Lin, Y. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.09.013 · Cited by 22 · see citing works
eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior
Ma, X., Li, L., Li, Z., Huang, Z., Yang, Y., Liu, P., Guo, D., Li, Y., Wu, T., Luo, R., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154543 · Cited by 25 · see citing works
“5 Sprague Dawley (SD) rat embryos as previously described (Xiao et al , 2013; Huang et al , 2020).”
Self-citationThompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
Zhu, S., Hou, S., Lu, Y., Wei, S., Cui, Z., Dong, T., Feng, H., & Wan, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.638477 · Cited by 16 · see citing works
Roles of Rac1-Dependent Intrinsic Forgetting in Memory-Related Brain Disorders: Demon or Angel
Wang, W., Wang, Z., Cao, J., Dong, Y., & Chen, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310736 · Cited by 11 · see citing works
Rac1/PAK1 signaling contributes to bone cancer pain by Regulation dendritic spine remodeling in rats
Xu, L., Yang, L., Wu, Y., Wan, X., Tang, X., Xu, Y., Chen, Q., Liu, Y., & Liu, S. (2023) · Molecular Pain · doi:10.1177/17448069231161031 · Cited by 12 · see citing works
Self-citationLi, Y., Deng, P., Chen, C., Ma, Q., Pi, H., He, M., Lu, Y., Gao, P., Zhou, C., He, Z., et al. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.771508 · Cited by 10 · see citing works
“This model has been proved to be efficient in several studies (22, 60).”
BackgroundMethodTet2 acts in the lateral habenula to regulate social preference in mice
Xu, X., Zhou, H., Wu, H., Miao, Z., Wan, B., Ren, H., Ge, W., Wang, G., & Xu, X. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112695 · Cited by 9 · see citing works
Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly
Herbst, C., Bothe, V., Wegler, M., Axer-Schaefer, S., Audebert-Bellanger, S., Gecz, J., Cogne, B., Feldman, H. B., Horn, A. H. C., Hurst, A. C. E., et al. (2024) · Human Genetics · doi:10.1007/s00439-024-02655-4 · Cited by 7 · see citing works
“…to the recommendations of ClinGen (Strande et al. 2017), including the experimental evidence of the published cell culture studies (Ueda et al. 1993; Huang et al. 2019), mouse studies (Guo et al. 2021) and the cohort of the present study, would result in supporting evidence of moderate level.”
BackgroundAnimal models of developmental dyslexia: Where we are and what we are missing
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DOCK4 is a Novel Prognostic Biomarker and Correlated with Immune Infiltrates in Colon Adenocarcinoma
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THEMIS2 contributes to ovarian cancer metastasis via DOCK4-mediated activation of Rap1 signaling
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“DOCK4 facilitates Rap1 and Rac1 activation, playing roles in dendritic spine formation [ 20 ], maintains adherens junction necessary for lung vascu - lar barrier integrity [ 21 ], and promoting migration in MDA-MB-231 breast cancer cells [ 22 ].”
Guo, D., Yang, X., Gao, M., Chen, X., Tang, Y., Shen, L., Li, K., & Shi, L. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01233-4 · Cited by 5 · see citing works
Self-citationGenetic Modifications of Developmental Dyslexia and Its Representation Using In Vivo, In Vitro Model
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Presynaptic Rac1 in the hippocampus selectively regulates working memory
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“Consistent with Rac1’s important roles in synaptic signaling, mutations of Rac1 or alterations to its signaling pathways are associated with a variety of neurological disorders ( Fatemi et al., 2013 ; Hayashi-Takagi et al., 2010 ; Huang et al., 2020 ).”
BackgroundAlmuwaqqat, Z., Liu, C., Kim, J. H., Hammadah, M., Alkhoder, A. A., Raggi, P., Shah, A. J., Bremner, J. D., Vaccarino, V., Sun, Y. V., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-54566-z · Cited by 3 · see citing works
“The DOCK protein family plays a role in vascular smooth muscle cell (VSMC) migration through bone morphogenic protein 4 and miRNA 21 25 , in the morphogenesis of blood vessels 26 , and neural and synaptic development 27 .”
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“Moreover, studies have demonstrated that the rs2074130 and rs2217262 polymorphisms of DOCK4 are associated with the risk of autism [14] and schizophrenia [15], respectively.”
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Ras-related C3 botulinum toxin substrate 1 role in pathophysiology of neurological diseases
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Presynaptic Rac1 in the hippocampus selectively regulates working memoryPreprint
Kim, J., Bustamante, E., Sótonyi, P., Maxwell, N. D., Parameswaran, P., Kent, J. K., Wetsel, W. C., Soderblom, E. J., Rácz, B., & Soderling, S. H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.18.585488 · Cited by 1 · see citing works
Presynaptic Rac1 in the hippocampus selectively regulates working memoryPreprint
Kim, J., Bustamante, E., Sótonyi, P., Maxwell, N. D., Parameswaran, P., Kent, J. K., Wetsel, W. C., Soderblom, E. J., Rácz, B., & Soderling, S. H. (2024) · eLife · doi:10.7554/elife.97289.1 · Cited by 1 · see citing works
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Kim, J., Bustamante, E., Sotonyi, P., et al. (2024) · eLife · doi:10.7554/elife.97289.1.sa1
eLife Assessment: Presynaptic Rac1 in the hippocampus selectively regulates working memory
Scharfman, H. E. (2024) · eLife · doi:10.7554/elife.97289.1.sa2
Presynaptic Rac1 in the hippocampus selectively regulates working memory
Kim, J., Bustamante, E., Sótonyi, P., Maxwell, N. D., Parameswaran, P., Kent, J. K., Wetsel, W. C., Soderblom, E. J., Rácz, B., & Soderling, S. H. (2024) · eLife · doi:10.7554/elife.97289.2
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Developmental Dyslexia and the Evolution of Adaptive Mammalian TraitsPreprint
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“Experimental studies have shown that autism-associated DOCK4 variants impair Rac1/Rap1 signaling, neurite outgrowth, and dendritic spine develop - ment, reinforcing the biological importance of DOCK4 in neurodevelopment despite the absence of significant asso - ciation in the present cohort [30].”
Chrzanowska, J., Karpiński, P., Szczygieł, M., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10974535/v1
- Authors
- Huang, M., Liang, C., Li, S., Zhang, J., Guo, D., Zhao, B., Liu, Y., Peng, Y., Xu, J., Liu, W., Guo, G., & Shi, L.
- Affiliations
- Jinan University (CN)
- Hong Kong University of Science and Technology (HK)
- Zhejiang University (CN)
- Corresponding author
- Shi, Lei
- ORCID
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2020-01-15
- Volume
- 13
- Pages
- 577-577
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC6974517
- OpenAlex
- W2999488066
- Semantic Scholar
- fcec833e77897c0156de56893bc9ad8c8b425b0f
- Cited by
- 41
- References
- 33
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 13 · 2023: 8 · 2022: 3 · 2021: 11 · 2020: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81761130084)
- Newton Fund (AOMS-NAF005100)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Social Sciences › Psychology › Developmental and Educational Psychology › Reading and Literacy Development
- Keywords
- DOCK4, autism spectrum disorder, dyslexia, Rac1, Rap1, guanine nucleotide exchange factor, exon deletion, neurite outgrowth, dendritic spine formation, excitatory synaptic transmission, cytoskeleton, neuronal development, neurodevelopmental disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-14.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-14.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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