The Serine/Threonine Kinase NDR2 Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus

NDR1 expression remains completely absent in the mouse brain.

“NDR2 expression is low after birth and steadily increases during postnatal development, whereas NDR1 expression remains completely absent.”

• cites Demiray et al. 2018 sourceCould not verify

  The Introduction (page not provided) identifies Ndr1 as a close homolog of Ndr2 but does not say whether Ndr1 is expressed in the mouse brain. Searches for Ndr1 expression and postnatal development found no passage establishing that its expression remains absent. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourceDisputed

  The Results section (‘TGNdr2 expression in the hippocampus’; page not provided) says Ndr1 is endogenously expressed in mouse dentate gyrus granule cells. That directly contradicts the claim that NDR1 expression is completely absent from the mouse brain. (LLM, conf=0.95)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

NDR2 is the only NDR kinase expressed in the adult mouse brain.

“Previously, we showed that from the mammalian NDR kinases, NDR2 is the only one expressed in the adult mouse brain.”

• cites Demiray et al. 2018 sourcePartly supported

  The Introduction (page unavailable) reports prominent Ndr2 expression in the central nervous system. It does not establish that Ndr2 is the only NDR kinase expressed in the adult mouse brain; the passages found do not compare adult-mouse-brain expression across the kinase family. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourceDisputed

  The Results section (“TGNdr2 expression in the hippocampus”) says that both Ndr2 and its close homolog Ndr1 are endogenously expressed in wild-type dentate gyrus granule cells. The Methods specify that the expression measurements included mice at 3 months of age, contrary to the claim that NDR2 is the only NDR kinase expressed in the adult mouse brain. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

NDR2-dependent phosphorylation of Filamin A at Serine2152 displaces Filamin A from the β1 integrin cytoplasmic tail.

“The mechanism involves the displacement of Filamin A from the β1 integrin cytoplasmic tail upon NDR2‐dependent phosphorylation of Filamin at Serine2152”

• cites Waldt et al. 2018 sourceDisputed

  The Discussion says Ndr2-dependent phosphorylation of Filamin A at S2152 releases it from LFA-1. The Introduction identifies the relevant cytoplasmic tail as that of LFA-1’s β2 chain (CD18), not a β1 integrin tail. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

NDR2 phosphorylates Filamin A at S2152, promoting its dissociation from the integrin tail domain.

“Within this signaling cascade, NDR2 appears as a key regulator by phosphorylating Filamin A at the S2152, consistent with its phosphorylation motif, thereby promoting its dissociation from the integrin tail domain (Waldt et al. 2018).”

• cites Waldt et al. 2018 sourceSupported

NDR2 is the principal NDR kinase in the mouse CNS.

“NDR2 is the principal NDR kinase in the mouse CNS, where it has been shown to regulate integrin‐dependent dendritic branching as well as growth and plasticity in hippocampal mossy fibers.”

• cites Demiray et al. 2018 sourcePartly supported

  The Introduction (page unavailable) describes prominent Ndr2 expression in the central nervous system. It does not establish that Ndr2 is the principal NDR kinase in the mouse CNS relative to other family members. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourceSupported

Phosphorylation of the T788/789 motif promotes β1 integrin activation.

“This activation is further promoted by the phosphorylation of the T788/789 motif (inside‐out signaling) (Kiema et al. 2006).”

• cites Kiema et al. 2006 sourcePartly supported

  The Results section shows that phospho-mimicking mutations in β7 threonines reduce filamin binding without impairing talin binding. The Discussion only speculates that phosphorylation might thereby modulate integrin activation; it does not show that phosphorylation of the β1 T788/789 motif promotes β1 activation. Page numbers were not available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

NDR2 controls dendritic branching during the postnatal development of pyramidal neurons in hippocampal area CA3.

“We showed that it controls the dendritic branching during the postnatal development of pyramidal neurons in hippocampal area CA3, growth, and plasticity of hippocampal mossy fibres (Demiray et al. 2018;”

• cites Demiray et al. 2018 sourcePartly supported

  The Results section, “Ndr2 Controls Dendritic Branching in Primary Neurons” (page unavailable), shows that changing Ndr2 expression affects dendritic branching in cultured hippocampal neurons. The Methods section, “Primary Cell Culture” (page unavailable), identifies those neurons as derived from embryonic mouse hippocampi; the cited study does not establish the claim specifically for postnatal CA3 pyramidal neurons. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourcePartly supported

  The Introduction reports altered basal and apical dendrites in CA3 pyramidal neurons of Ndr2-knockout mice, supporting a role for Ndr2 in their dendritic growth. It describes those neurons in adulthood, however, and does not establish that Ndr2 controls their branching during postnatal development. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In developing neurons, the dendritic growth effects of NDR2 are at least in part mediated by control of intracellular trafficking and recycling of β1 integrins.

“In developing neurons, the dendritic growth effects of NDR2 are at least in part mediated by a control in the intracellular trafficking and recycling of β1 integrins (Rehberg et al. 2014; Demiray et al. 2018).”

• cites Rehberg et al. 2014 sourceSupported
• cites Demiray et al. 2018 sourceSupported

NDR2 expression is low after birth and steadily increases during postnatal development in the mouse brain.

“NDR2 expression is low after birth and steadily increases during postnatal development, whereas NDR1 expression remains completely absent.”

• cites Demiray et al. 2018 sourceCould not verify

  The Introduction describes prominent Ndr2 expression in the central nervous system, but gives no expression levels at birth or postnatal time course. Searches for postnatal expression and developmental changes found no passage establishing a steady increase in the mouse brain. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourcePartly supported

  The Results report that endogenous Ndr2 expression increases during postnatal development in mouse dentate gyrus granule cells. But the Discussion specifies that levels fell from P15 to P30 before rising in adulthood, so the measured trajectory was not steady; the paper also does not establish expression levels immediately after birth. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Filamin A controls the avidity and affinity of β1-containing integrins by enhancing their trafficking and presentation at the cell surface and their clustering.

“Filamin A is a critical factor controlling the avidity and affinity of β1 containing integrins, as it enhances their trafficking and presentation at the cell surface as well as their clustering (Truong et al. 2015).”

• cites Truong et al. 2015 sourcePartly supported

  The Introduction (page unavailable) says filamin helps recycle integrins to the cell membrane, increasing surface expression, and that its binding sites facilitate integrin clustering. It also says filamin binds β1 integrins, but does not establish that filamin A controls the avidity or affinity of β1-containing integrins through those mechanisms. The paper’s simulations instead examine αIIbβ3 integrin. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

NDR2 controls growth and plasticity of hippocampal mossy fibres.

“We showed that it controls the dendritic branching during the postnatal development of pyramidal neurons in hippocampal area CA3, growth, and plasticity of hippocampal mossy fibres (Demiray et al. 2018;”

• cites Demiray et al. 2018 sourcePartly supported

  The Results section, “Ndr2 Controls Dendritic Branching in Primary Neurons” (page unavailable), shows that Ndr2 affects dendritic growth in cultured hippocampal neurons. The Introduction also reports earlier findings on hippocampal axonal growth. Neither passage establishes that Ndr2 controls the growth or plasticity of hippocampal mossy fibres specifically. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites Madencioglu et al. 2021 sourcePartly supported

  The Discussion says Ndr2-related signaling may alter mossy-fiber growth in adult-born granule cells. The Results report reduced late-phase mossy-fiber LTP in the ventral hippocampus of Ndr2-overexpressing mice, but no change in short-term plasticity or comparable change in dorsal mossy fibers. Thus, the unqualified claim that NDR2 controls mossy-fiber growth and plasticity is broader and more certain than the paper’s findings. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

T788/789 phosphorylation ultimately enhances neurite outgrowth.

“ultimately enhancing neurite outgrowth (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourceSupported

T788/789 phosphorylation promotes the recognition of integrin substrates such as fibronectin.

“promotes the recognition of integrin substrates such as fibronectin”

• cites Rehberg et al. 2014 sourcePartly supported

  The Results section (‘Ndr2 controls β1-integrin phosphorylation at Thr 788/789’; page unavailable) reports increased phosphorylation at that site, and the Discussion links the motif to proteins involved in integrin activation. The paper uses fibronectin-coated cultures, but does not show that Thr 788/789 phosphorylation promotes recognition of fibronectin; the Discussion says a high-affinity conformation also requires intracellular binding partners. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

NDR2 controls integrin-dependent neurite growth.

“We previously demonstrated that NDR2 controls integrin‐dependent neurite growth and integrin trafficking, and its expression modulates the phosphorylation levels of T788/789 on the β1 integrin subunit (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourceSupported

NDR2 contributes to the T788/789 phosphorylation of the β1 integrin cytoplasmic tail.

“We previously observed that NDR2 contributes to the T788/789 phosphorylation of β1 integrin cytoplasmic tail (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourceSupported

NDR2 expression modulates phosphorylation levels of T788/789 on the β1 integrin subunit.

“its expression modulates the phosphorylation levels of T788/789 on the β1 integrin subunit (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourceSupported

T788/789 phosphorylation increases the recruitment of β1 integrins to the cell surface.

“increases the recruitment of β1 integrins to the cell surface”

• cites Rehberg et al. 2014 sourceSupported

NDR2 controls integrin trafficking.

“We previously demonstrated that NDR2 controls integrin‐dependent neurite growth and integrin trafficking, and its expression modulates the phosphorylation levels of T788/789 on the β1 integrin subunit (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourceSupported

These data align with the role of integrin signaling in sustaining synaptic plasticity at the SC-CA1 synapse.

“Together, these data align well with the role of integrin signaling in sustaining synaptic plasticity at the SC‐CA1 synapse (Brzdąk et al. 2023) and suggest that NDR2 is a critical component in sustaining LTP via supporting β1 integrin‐mediated signaling.”

• cites Brzdąk et al. 2023 sourcePartly supported

  The Discussion (page not available) reports that interfering with integrins abolished LTP of excitatory transmission and that β1-integrin loss weakened NMDAR-dependent LTP. The paper’s own results concern inhibitory synapses onto CA1 interneurons; the cited passage does not establish that integrin signaling sustains plasticity specifically at the SC–CA1 synapse. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Stimulation of NDR2 activity leads to T788/789 phosphorylation of β1 integrins.

“While stimulation of NDR2 activity leads to T788/789 phosphorylation of β1 integrins, this phosphorylation appears to be indirect.”

• cites Rehberg et al. 2014 sourceSupported

NDR2 is a critical component in sustaining LTP via supporting β1 integrin-mediated signaling.

“Together, these data align well with the role of integrin signaling in sustaining synaptic plasticity at the SC‐CA1 synapse (Brzdąk et al. 2023) and suggest that NDR2 is a critical component in sustaining LTP via supporting β1 integrin‐mediated signaling.”

• cites Brzdąk et al. 2023 sourcePartly supported

  The Results section (“α5β1 integrins are involved in NMDAR-dependent iLTP in SST + INs”; page unavailable) reports that interfering with α5β1 integrins abolished inhibitory long-term potentiation in CA1 interneurons. The Discussion (“Cell-specificity of GABAergic plasticity is associated with integrin-dependent mechanisms”; page unavailable) also reports prior evidence linking integrins to excitatory LTP, but this paper does not establish the cited role specifically at the SC–CA1 synapse. The sentence presents NDR2’s role as the citing authors’ own inference, not as a finding attributed to Brzdąk et al. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: The control GRADSP peptide is inert with respect to integrin activation.

Displacement of Filamin A from the β1 integrin cytoplasmic tail is crucial for the activation and stabilization of membrane integrin complexes.

“a step crucial for the activation and stabilization of membrane integrin complexes (Waldt et al. 2018)”

• cites Waldt et al. 2018 sourcePartly supported

  The Introduction (page not provided) says that Filamin A dissociation is a critical step in activating LFA-1 in T cells, and the Abstract says subsequent Talin and Kindlin-3 binding stabilizes its open conformation. The claim instead specifies a β1 integrin tail; the paper identifies the tail as β2 (CD18) and does not establish the claim for membrane integrin complexes generally. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Filamin A is a substrate of NDR2.

“We previously demonstrated that Filamin A, which transduces mechanical signals to the cell through the actin cytoskeleton and modulation of integrin activity, is a substrate of NDR2.”

• cites Waldt et al. 2018 sourceSupported

Phosphorylation of β1 integrin by NDR kinases requires Calcium-calmodulin kinase II and Protein kinase C activity.

“a requirement Calcium‐calmodulin kinase II and Protein kinase C activity (Rehberg et al. 2014)”

• cites Rehberg et al. 2014 sourcePartly supported

  The ‘Ndr2 controls β1-integrin phosphorylation at Thr 788/789’ section reports that Ndr2-induced phosphorylation in HEK-293T cells was sensitive to CaMKII and PKC inhibitors. It also reports that Ndr2 did not phosphorylate β1-integrin directly; the finding concerns Ndr2, not NDR kinases generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In an in vitro kinase assay targeting the β1 integrin cytoplasmic tail as substrate, there is no direct phosphorylation of β1 integrin by NDR kinases.

“there is no direct phosphorylation of the β1 integrin by NDR kinases”

• cites Rehberg et al. 2014 sourcePartly supported

  The section “Ndr2 controls β1-integrin phosphorylation at Thr 788/789” reports that Ndr2 did not directly phosphorylate the β1-integrin cytoplasmic domain in an in vitro kinase assay; the Figure 4 caption reports the same result. The experiments described test Ndr2, not NDR kinases generally, so the plural wording extends beyond what this source establishes. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The reduced long-term potentiation in Ndr2-deficient mice can be restored by activation of integrins with an arginine-glycine-aspartate-containing peptide.

“This reduction is associated with decreased synaptic density in both conditions and accompanied by reduced long‐term potentiation in the synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells, which could be restored by activation of integrins with an arginine‐glycine‐aspartate‐containing peptide, as well as with mild spatial memory deficits.”

Ndr2 deficiency is associated with decreased synaptic density in hippocampal area CA1 and in primary hippocampal neurons in vitro.

“This reduction is associated with decreased synaptic density in both conditions and accompanied by reduced long‐term potentiation in the synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells, which could be restored by activation of integrins with an arginine‐glycine‐aspartate‐containing peptide, as well as with mild spatial memory deficits.”

Ndr2 deficiency is accompanied by mild spatial memory deficits.

“This reduction is associated with decreased synaptic density in both conditions and accompanied by reduced long‐term potentiation in the synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells, which could be restored by activation of integrins with an arginine‐glycine‐aspartate‐containing peptide, as well as with mild spatial memory deficits.”

Ndr2 deficiency is accompanied by reduced long-term potentiation at synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells.

“This reduction is associated with decreased synaptic density in both conditions and accompanied by reduced long‐term potentiation in the synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells, which could be restored by activation of integrins with an arginine‐glycine‐aspartate‐containing peptide, as well as with mild spatial memory deficits.”

Ndr2 deficiency reduces T788/789 phosphorylated β1 integrin expression at synaptic sites in hippocampal area CA1 and in primary hippocampal neurons in vitro.

“In this study, using constitutive NDR2 null mutant mice, we demonstrate that Ndr2 deficiency leads to a reduction of T788/789 phosphorylated β1 integrin expression at synaptic sites both in the hippocampal area CA1 and in primary hippocampal neurons in vitro.”

The WCM deficit in Ndr2 KO mice is overcome with another day of training.

“This deficit could be overcome with another day of training in the task (Figure 4B).”

pβ1 levels are decreased in the CA1 area of the dorsal hippocampus in Ndr2 KO adult mice.

“Immunohistochemistry of the dorsal hippocampus from adult mice further confirmed the decreased pβ1 levels in Ndr2 KO mice in neurons of the CA1 area (t = 2.191, df = 14, p = 0.045).”

• Also stated in: § Ndr2 Deficiency Leads to a Reduction of Activated β1 Integrins at Synapses · plain

  “Quantification in the CA1 neurons confirms the reduced phospho‐β1 Integrin labeling in vivo, n = 8 mice each.”

In the MWM probe trial, there is no difference between WT and Ndr2 KO mice.

“Nonetheless, during the probe trial, when the platform was removed and the mice were left to swim freely for the duration of the test, no differences between the WT and KO mice were observed (t = 1.144, df = 26, p = 0.263) (Figure 4E)”

NDR2 deficiency impairs high-frequency stimulation-induced LTP at CA3-CA1 synapses.

“However, we observed an impaired LTP induced by a high‐frequency stimulation (HFS) protocol in the KO mice compared to WT littermates (Figure 3C) (F 69,1750 = 1.777, p < 0.0001).”

In the detailed spine-shape analysis, the proportion of mushroom spines is reduced in CA1.

“A detailed analysis reveals a reduction in the proportion of mushroom spines in CA1 and an increase of thin spines in basal CA3.”

In the detailed spine-shape analysis, thin spines are increased in basal CA3.

“A detailed analysis reveals a reduction in the proportion of mushroom spines in CA1 and an increase of thin spines in basal CA3.”

In reversal training 1 week later, accuracy of finding the platform is the same between WT and Ndr2 KO mice.

“Moreover, when reversal training was performed 1 week later, the accuracy of finding the platform was the same between the WT and the KO mice.”

NDR2 deficiency reduces phosphorylation/activation of integrin β1 in the dorsal hippocampal CA1.

“reduced phosphorylation of integrin β1 and spine density in the dorsal hippocampal CA1”

• Also stated in: § Ndr2 Deficiency Leads to Impaired LTP in CA1 That Can Be Rescued by Integrin Stimulation · plain

  “observed reduction in activated integrin levels in this region”

NDR2 deficiency increases the composition of mushroom spines in CA1 apical and basal dendrites.

“There was a significant increase in the composition of mushroom spines in both apical (t = 2.128, df = 36, p = 0.0403) and basal (t = 2.157, df = 36, p = 0.0378) dendrites in the CA1 (Fig of the KO mice (2F)).”

Ndr2 KO mice show decreased accuracy in the WCM on the 4th day of training compared with WT mice.

“In the WCM (Figure 4A), Ndr2 KO mice displayed a decreased accuracy in entering the arm with the escape platform on the 4th day of training (F 12,120 = 1.910, p = 0.0395) compared to the WT mice.”

There was no genotype-specific difference in paired-pulse facilitation between Ndr2 WT and KO mice.

“Irrespectively of considering sex as a covariate or not, there was no genotype‐specific difference in basal synaptic transmission and paired‐pulse facilitation, but there was a significant difference in long‐term potentiation between genotypes.”

In vivo Golgi-Cox analysis shows that NDR2 deficiency reduces spine numbers in CA1 pyramidal neurons in both apical and basal dendrites.

“Similar to our observations in vitro, we found a reduction in spine numbers in the CA1 pyramidal neurons, both in apical (t = 2.605, df = 6, p = 0.0404) and basal (t = 3.299, df = 6, p = 0.016) dendrites.”

NDR2 deficiency does not alter short-term plasticity assessed by paired-pulse stimulation at CA3-CA1 synapses.

“Similarly, we did not observe any alterations in the short‐term plasticity assessed by paired‐pulse stimulation at different stimulation intervals (Figure 3B) (F 4,105 = 0.1082, p = 0.9794).”

Total β1 staining is not changed in Ndr2 KO mice compared to WT.

“No changes were observed in total β1 staining (t = 0.871, df = 10, p = 0.404)”

There was no genotype-specific difference in basal synaptic transmission between Ndr2 WT and KO mice.

“Irrespectively of considering sex as a covariate or not, there was no genotype‐specific difference in basal synaptic transmission and paired‐pulse facilitation, but there was a significant difference in long‐term potentiation between genotypes.”

The control GRADSP peptide does not rescue the LTP deficit in Ndr2 KO mice.

“while treatment with the control GRADSP peptide did not induce any rescue effect (Figure 3E).”

• Also stated in: § Ndr2 Deficiency Leads to Impaired LTP in CA1 That Can Be Rescued by Integrin Stimulation · plain

  “Control GRADSP peptide does not rescue the LTP deficit in the KO mice, n = 8 (WT); 7 (KO) mice.”

The composition of the remaining spine types, including thorny excrescences, does not differ between WT and Ndr2 KO mice in apical or basal CA1 and CA3 neurons.

“The composition of the rest of the spines, including the thorny excrescences, was not different between the WT and KO mice for any kind of spine or neuron: apical CA1 (F 1,6 = 0.5226, p = 0.4969), basal CA1 (F 1,6 = 0.3796, p = 0.5618), apical CA3 (F 1,6 = 0.999, p = 0.3559), or basal CA3 (F 1,6 = 0.0000, p = 0.9999).”

The number of double-positive synaptic clusters (Synaptophysin/PSD95) is significantly decreased in Ndr2 KO neurons compared to WT.

“revealed a significant decrease in the number of double‐positive synaptic clusters in Ndr2 KO neurons compared to the WT.”

• Also stated in: § Ndr2 Deficiency Leads to a Deficit in Synapse Number and Maturation · plain

  “reveals a significant reduction of double positive puncta in Ndr2 KO cells as compared to WT cells.”

There was a significant difference in long-term potentiation between Ndr2 WT and KO mice.

“Irrespectively of considering sex as a covariate or not, there was no genotype‐specific difference in basal synaptic transmission and paired‐pulse facilitation, but there was a significant difference in long‐term potentiation between genotypes.”

There is a significant genotype × treatment interaction in LTP when GRGDSP- and GRADSP-treated slices are compared.

“Normalization of LTP by the GRGDSP peptide was also evident when the last 10 min of LTP data were compared between different treatments, with a significant genotype × treatment interaction (F 2,52 = 3.749, p = 0.03011) (Figure 3F).”

Pharmacological activation of integrins with GRGDSP peptide restores LTP in Ndr2 KO mice.

“Treatment with the GRGDSP peptide (Figure 3D) was sufficient to restore LTP in Ndr2 KO mice (F 69,1190 = 0.4652, p > 0.9999)”

• Also stated in: § Ndr2 Deficiency Leads to Impaired LTP in CA1 That Can Be Rescued by Integrin Stimulation · plain

  “Pharmacological activation of integrins via GRGDSP peptide normalizes LTP in the KO mice, n = 8 mice.”

pβ1 levels at spines of Ndr2 KO hippocampal neurons are significantly decreased compared to WT.

“observed an overall significant decrease in pβ1 levels at the spines of KO hippocampal neurons compared to WT (F 1,18 = 27.9, p < 0.0001)”

• Also stated in: § Ndr2 Deficiency Leads to a Reduction of Activated β1 Integrins at Synapses · plain

  “Quantification of the phospho‐β1 Integrin signal in the spines reveals a significant reduction in Ndr2 KO mice.”

NDR2 deficiency does not affect spine density in CA3 pyramidal neurons in either apical or basal dendrites.

“By contrast, NDR2 deficiency did not affect the spine density either in the apical (t = 0.276, df = 6, p = 0.791) or basal (t = 0.5882, df = 6, p = 0.577) CA3 neurons (Figure 2D).”

No NDR1 expression is detected in either Ndr2 WT or KO dorsal hippocampus samples.

“No NDR1 expression was detected in either genotype”

The decrease in pβ1 levels at spines of Ndr2 KO neurons does not depend on dendritic segment location (proximal vs distal).

“regardless of the dendritic segment location (F 1,18 = 1.4, p = 0.247)”

The reduction in double-positive synaptic clusters in Ndr2 KO neurons is reversed back to control levels after NDR2 re-expression.

“Moreover, this reduction could be reversed back to control levels after NDR2 re‐expression (F 2,43 = 4.927, p = 0.018).”

• Also stated in: § Ndr2 Deficiency Leads to a Deficit in Synapse Number and Maturation · plain

  “KO cells are recovered to WT levels upon expression of EGFP:Ndr2.”

In the MWM probe trial, both WT and Ndr2 KO groups prefer to swim close to where the platform was located (escape quadrant).

“with both groups preferring to swim close to where the platform was located (escape quadrant).”

NDR2 deficiency does not alter baseline synaptic transmission at CA3-CA1 synapses.

“Analysis of input–output (I‐O) curves (Figure 3A) did not reveal any difference between WT and Ndr2 KO mice in the baseline synaptic transmission (F 10,275 = 0.1667, p = 0.9982).”

NDR2 gene expression is induced during memory consolidation.

“Moreover, the localization of NDR2 at synaptic sites and the induction of its gene expression during memory consolidation indicate a potential role in synaptic plasticity (Stork et al. 2004).”

• cites Stork et al. 2004 sourceNot checked — no full text of the source

NDR2 localizes at synaptic sites.

“Moreover, the localization of NDR2 at synaptic sites and the induction of its gene expression during memory consolidation indicate a potential role in synaptic plasticity (Stork et al. 2004).”

• cites Stork et al. 2004 sourceNot checked — no full text of the source

Integrins regulate synaptic plasticity, including long-term potentiation and various forms of memory.

“and most importantly, this regulation extends to synaptic plasticity, including long‐term potentiation and various forms of memory (Chan et al. 2006, 2003).”

• cites Chan et al. 2006, 2003Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

NDR2 is involved in integrin-dependent synapse formation and plasticity in the mouse hippocampus.

“Together, our results suggest that NDR2 is involved in integrin‐dependent synapse formation and plasticity in the mouse hippocampus.”

NDR2 deficiency plays a selective role in modulating synaptic plasticity in the CA1 region.

“This suggests that NDR2 deficiency plays a rather selective role in modulating synaptic plasticity in this region.”

NDR2 deficiency directly leads to reduced T788/789 phosphorylated Integrin β1 levels in both hippocampal dendritic spines in vitro and in the CA1 area in vivo.

“In summary, our findings demonstrate NDR2 deficiency directly leads to reduced T788/789 phosphorylated Integrin β1 levels in both hippocampal dendritic spines in vitro and in the CA1 area in vivo.”

The reduction in pβ1 staining intensity may be due to a relative decrease in phosphorylation of β1 integrin rather than decreased protein expression.

“indicating that the reduction in pβ1 staining intensity may be due to a relative decrease in phosphorylation of the β1 integrin rather than decreased protein expression (Figure S1).”

Absence of NDR2 does not result in protein expression of NDR1.

“showing that the absence of NDR2 does not result in protein expression of NDR1.”

The observed pT788/789 β1 integrin expression likely reflects an increased availability of activated integrins at hippocampal synapses.

“Thus, the observed pT788/789 β1 integrin expression is likely to reflect an increased availability of activated integrins at hippocampal synapses.”

Phosphorylation of β1 integrins by NDR2 appears to be indirect.

“this phosphorylation appears to be indirect”

• AssumptionRests on an assumption: β1 integrins do not display an NDR1/2 consensus motif.

Ndr2-deficient mice display reduced synaptic plasticity at the CA3-CA1 synapse.

“Ndr2 deficient mice display reduced synaptic plasticity in the CA3‐CA1 synapse.”

Ndr2 deficiency results in mild spatial memory deficits.

“Ndr2 Deficiency Results in Mild Spatial Memory Deficits”

Loss of the NDR2 homolog Trc or its regulator Fry in Drosophila disrupts both dendritic tiling and branching.

“Previous studies have shown that the loss of the NDR2 homolog Trc or its regulator Fry in Drosophila disrupts both dendritic tiling and branching (Emoto et al. 2004)”

• cites Emoto et al. 2004 sourceNot checked — no full text of the source

Finely tuned Hippo pathway regulation plays a critical role in cognitive function.

“Collectively, these findings highlight the critical role of finely tuned Hippo pathway regulation in cognitive function.”

NDR2 kinase is very well suited to translate various development and plasticity-related signals.

“Considering putative activation mechanisms of NDR2 at the synapse, it is evident that NDR2 kinase is very well suited to translate various development and plasticity‐related signals.”

Our results contribute to the growing body of evidence highlighting the significance of Hippo kinase NDR2 in integrating signals related to plasticity and cognition through the regulation of integrin signaling.

“In conclusion, our results contribute to the growing body of evidence highlighting the significance of Hippo kinase NDR2 in integrating signals related to plasticity and cognition through the regulation of integrin signaling.”

The activation mechanism of synaptic β1 integrins by NDR2 may involve the intermediate activation of other substrates.

“Moreover, the activation mechanism of synaptic β1 integrins by NDR2 may involve the intermediate activation of other substrates.”

Regulation of integrins via NDR2 plays an evolutionarily conserved role in specific aspects of neuronal morphology.

“This suggests that regulation of integrins via NDR2 plays an evolutionarily conserved role in specific aspects of neuronal morphology.”

NDR2 may modulate integrin trafficking and activation during synaptic development and plasticity through multiple substrates.

“NDR2 thus may modulate integrin trafficking and activation during synaptic development and plasticity through multiple substrates.”

NDR2 kinase is an intermediary player between upstream regulators such as MST kinases, MOB1, and KIBRA and downstream effectors such as integrin receptor activity that controls both synapse formation and memory processes.

“Consequently, NDR2 kinase emerges as an intermediary player between upstream regulators such as MST kinases, MOB1, and KIBRA and downstream effectors such as integrin receptor activity that controls both synapse formation and memory processes.”