MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system

In the paper

“There is a precedent for post-transcriptional regulation of miRNA expression [48,49], although this has not been demonstrated for different miRNAs from the same transcript.”

What the sources say

• Supported

  The Introduction says the authors provide evidence that mammalian miRNA expression can be regulated during processing. The discussion reports that differential processing of precursor miRNAs produces tissue- and developmental-specific expression. The citations attach to the precedent in the first clause, not to the citing authors’ qualification about different miRNAs from the same transcript. (LLM, conf=0.93)

  cites [48] Obernosterer G, Leuschner PJ, Alenius M, Martinez J: Post-transcriptional regulation of microRNA expression. Rna. 2006, 12: 1161-1167. 10.1261/rna.2322506. source
• Supported

  The Results and Discussion report that mature miRNA levels can differ from primary-transcript levels and identify regulated Drosha processing as a post-transcriptional mechanism. This supports the precedent for post-transcriptional regulation to which the citations are attached; the sentence’s same-transcript caveat is not presented as a finding from this source. (LLM, conf=0.92)

  cites [49] Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM: Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006, 20: 2202-2207. 10.1101/gad.1444406. source

In the paper

“These observations are consistent with the fact that proliferation and production of neurons continues into adulthood in the CNS of zebrafish [46,47].”

What the sources say

• Supported

  The Introduction states that proliferation and neurogenesis occur throughout life in teleost fish and identifies several sites where newborn neurons form in the adult zebrafish brain. This supports the claim about continued proliferation and neuron production in the zebrafish CNS; it does not imply that every CNS region produces neurons. (LLM, conf=0.93)

  cites [46] Adolf B, Chapouton P, Lam CS, Topp S, Tannhauser B, Strahle U, Gotz M, Bally-Cuif L: Conserved and acquired features of adult neurogenesis in the zebrafish telencephalon. Dev Biol. 2006, 295: 278-293. 10.1016/j.ydbio.2006.03.023. source
• ?Not checked — no full text of the sourcecites [47] Grandel H, Kaslin J, Ganz J, Wenzel I, Brand M: Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate. Dev Biol. 2006, 295: 263-277. 10.1016/j.ydbio.2006.03.040. source

In the paper

“Many of the genes in these pathways are implicated in human diseases [43].”

What the sources say

• Partly supported

  The Discussion states that mutations in IFT genes such as Tg737 cause developmental defects and disease, and the Introduction describes disease in Tg737 mutant mice. The copy does not establish that many IFT-pathway genes are implicated specifically in human diseases; its mention of human hydrocephalus does not identify the responsible genes as IFT genes. Page numbers were not available in the indexed passages. (LLM, conf=0.87)

  cites [43] Banizs B, Pike MM, Millican CL, Ferguson WB, Komlosi P, Sheetz J, Bell PD, Schwiebert EM, Yoder BK: Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development. 2005, 132: 5329-5339. 10.1242/dev.02153. sourceExperimental — accuracy not yet measured

In the paper

“A cluster on chromosome 8 contains both miR-181a and miR-181b but there is an additional copy of miR-181a on chromosome 22 and of miR-181b on chromosome 20 [19,44].”

What the sources say

• ?Could not verify

  The Results and Discussion discusses miRNA copy number and genomic locations, but the passages in our copy concern other miRNAs, not miR-181a or miR-181b. Searches for miR-181 and chromosomes 8, 20, and 22 found no passage establishing the claimed cluster or additional copies. (LLM, conf=0.73)

  cites [19] Ason B, Darnell DK, Wittbrodt B, Berezikov E, Kloosterman WP, Wittbrodt J, Antin PB, Plasterk RH: Differences in vertebrate microRNA expression. Proc Natl Acad Sci USA. 2006, 103: 14385-14389. 10.1073/pnas.0603529103. sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [44] Griffiths-Jones S: miRBase: the microRNA sequence database. Methods Mol Biol. 2006, 342: 129-138.

In the paper

“Localized translation from mRNAs is mediated in part by mRNA binding proteins that promote translation [59,60] and a counterpart to this could be that miRNAs clear mRNAs at sites where protein activity should be low.”

What the sources say

• ?Could not verify

  The Results and Discussion describe netrin-dependent localization of signaling proteins during axon formation, not mRNA-binding proteins that promote local translation. Searches for localized translation and RNA-binding proteins found no passage in our copy addressing that mechanism; the References list a separate study on local protein synthesis, but that does not establish the claimed mechanism. (LLM, conf=0.75)

  cites [59] Adler CE, Fetter RD, Bargmann CI: UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation. Nat Neurosci. 2006, 9: 511-518. 10.1038/nn1666. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says RNA-binding proteins localize mRNAs and can help regulate their translation. The Discussion proposes that Vg1RBP may activate β-actin translation, but presents that role as a possibility rather than an established mechanism, so the claim overstates this paper's evidence. (LLM, conf=0.82)

  cites [60] Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE: Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nat Neurosci. 2006, 9: 1247-1256. 10.1038/nn1775. sourceExperimental — accuracy not yet measured

In the paper

“Given that some mRNAs are localized and translated locally within neurons (for example, [57,58]), an attractive possibility is that cell-type specific brain miRNAs regulate spatially localized translation of proteins.”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Raab-Graham KF, Haddick PC, Jan YN, Jan LY: Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science. 2006, 314: 144-148. 10.1126/science.1131693. source
• Supported

  The Introduction describes mRNAs localized within dendrites and experimental support for their local translation. The Conclusion also states that mRNAs can be tethered and translated within axons, supporting the claim about local translation within neurons. (LLM, conf=0.94)

  cites [58] Piper M, Holt C: RNA translation in axons. Annu Rev Cell Dev Biol. 2004, 20: 505-523. 10.1146/annurev.cellbio.20.010403.111746. source

In the paper

“Certainly, recent studies suggest that there is a huge variability in the level of transcription at equivalent active loci in different cells [55] and perhaps there is comparable variability at repressed loci.”

What the sources say

• Partly supported

  The Discussion reports large cell-to-cell variation in mRNA levels, and the Results attribute it to random bursts of gene activation. Those passages support variability in transcription of the same genes across cells, but they do not establish huge variation in transcription levels specifically among loci that are all active. The sentence’s speculation about repressed loci is not attributed to this source. (LLM, conf=0.84)

  cites [55] Raj A, Peskin CS, Tranchina D, Vargas DY, Tyagi S: Stochastic mRNA synthesis in mammalian cells. PLoS Biol. 2006, 4: e309-10.1371/journal.pbio.0040309. sourceExperimental — accuracy not yet measured

In the paper

“It is intriguing that the translation of beta-actin in neuronal processes is regulated by Vg1RBP, a protein that binds the 3' UTR of mRNAs [60] and may, therefore, shield the mRNA from miRNAs.”

What the sources say

• Partly supported

  The Results section on Vg1RBP in retinal growth cones reports that Vg1RBP associates with β-actin mRNA, and the reporter-synthesis Results show that the β-actin 3′ UTR is needed for netrin-1-induced local protein synthesis. But the Discussion presents Vg1RBP's activation of β-actin translation as a possibility, not an established mechanism. The citation therefore supports the association and UTR-related context, but overstates direct regulation by Vg1RBP. (LLM, conf=0.84)

  cites [60] Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE: Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nat Neurosci. 2006, 9: 1247-1256. 10.1038/nn1775. sourceExperimental — accuracy not yet measured

In the paper

“mRNAs can be protected from miRNA attack as seen, for instance, in germ cells [7], although we are unaware of examples of such regulation occurring within different cellular compartments.”

What the sources say

• Supported

  The Discussion reports that elements in the nanos1 3′ UTR allow expression in zebrafish primordial germ cells despite miRNA-mediated repression. This supports protection from the miRNA’s repressive effects, though the Results clarify that the mRNA remains accessible to miRNAs rather than being physically shielded from them. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [7] Mishima Y, Giraldez AJ, Takeda Y, Fujiwara T, Sakamoto H, Schier AF, Inoue K: Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430. Curr Biol. 2006, 16: 2135-2142. 10.1016/j.cub.2006.08.086. source

In the paper

“For instance, in zebrafish, miR-430 targets a large number of maternally deposited transcripts at the onset of zygotic transcription [6] and many examples of spatially exclusive expression domains of miRNAs and their targets have been documented (for example, [12,53]).”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM: Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005, 123: 1133-1146. 10.1016/j.cell.2005.11.023. source
• Supported

  In “MiR-9a inhibits Sens expression in non-SOP cells” (page not available), the paper says miRNAs and their targets are often expressed in adjacent cells and presents miR-9a and Sens as an experimental example. This supports the cited statement about documented spatially distinct expression patterns. (LLM, conf=0.86)

  cites [53] Li Y, Wang F, Lee JA, Gao FB: MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila. Genes Dev. 2006, 20: 2793-2805. 10.1101/gad.1466306. source

In the paper

“In contrast, miR-34 expression is absent from forebrain and midbrain and present only in the caudal ventral and lateral isthmus and hindbrain, including ventral and lateral medulla oblongata cells (MO in Figure 5c), presumptive octaval area (OA in Figure 5c), reticular formation cells (intermediate reticular formation-(IMRF) and Mauthner cell (MAC) in Figure 5c; Additional data file 5, and Table D”

In the paper

“miR-182 and miR-96 show almost identical expression patterns to miR-183 (Figure 2f,g; and Table E in Additional data file 27), although expression is not as robust.”

In the paper

“This pattern is highly reminiscent of expression of the huC gene (Figure 2i), which encodes an RNA binding protein expressed in nearly all CNS neurons but the same subsets of retinal cells as miR-181a and miR-181b.”

In the paper

“Like miR-92b, let-7b expression is restricted to the CMZ of the retina, with expression absent from all mature retinal neurons (arrow in Figure 2b); let-7b has broader expression elsewhere in the larval brain (Additional data file 23).”

In the paper

“The expression of these miRNAs in peripheral sensory neural cells overlaps with miR-200a (Additional data file 16), although miR-200a lacks the CNS and cranial ganglia expression sites common to miR-183, miR-182 and miR-96 (Table E in Additional data file 27).”

In the paper

“Expression is not ubiquitous in neural cells as some areas such as the epithalamus and hypothalamic lateral torus are devoid of expression (Additional data files 2 and 3, and Table A in Additional data file 27).”

In the paper

“Both miRNAs are also expressed in migrated pretectal (M1 in Figure 4a,b) and tectal cells (TeO in Figure 4a,b) and more weakly in many differentiating cells throughout the brain, with some stronger sites of expression in central pallium and medulla oblongata (Additional data files 13 and 14, and Table C in Additional data file 27).”

In the paper

“Similarly showing conserved expression over time, miR-124 expression is excluded from periventricular cells and is detected in most differentiated cells throughout the adult brain as in the larval brain (compare Vd in Figure 1h and Sd in Figure 1b; Additional data file 7, and Tables B and G in Additional data file 27).”

In the paper

“For instance, miR-222 and miR-221 share largely similar expression in the adult hypothalamus (ATN, LH, Hd in Figure G of Additional data file 20 and Figure O of Additional data file 19) but only miR-222 is expressed in the ventral intermediate hypothalamus at the larval stage (Figure D of Additional data file 20 and Figure B of Additional data file 19; see also Table K in Additional data file 28”

In the paper

“Additionally, within the retina miR-9 is expressed in maturing cells of the CMZ (which are likely to still be proliferative) but expression is maintained only in amacrine cells of the inner nuclear layer (INL in Figure 2d).”

In the paper

“miR-181a and miR-181b show similar expression in the larval brain, and this is largely conserved to adult stages (although there is down-regulation in some areas such as thalamus and tegmentum; Additional data files 13 and 14, and Tables C and H in Additional data file 27).”

In the paper

“miR-183 is expressed in retinal photoreceptors and weakly in some inner nuclear layer cells, pineal cells that are again likely to be photoreceptors (Figure 2e) and perhaps also in parapineal photoreceptors (Figure C in Additional data file 15).”

In the paper

“Some of the miRNA expression patterns helped us annotate larval fish brain nuclei.”

In the paper

“For example, larval ventral thalamus (VT in Figure 5a) expresses miR-219 but the corresponding adult thalamic nuclei do not (ventrolateral (VL) and ventromedial (VM) in Figure 5b).”

In the paper

“Conversely, in adults, miR-219 is expressed in cells, possibly glia, associated with major tracts such as the lateral olfactory tract, post-optic commissure/optic chiasma and tract (poc and OT, respectively, in Figure 5b) whereas the equivalent pathways in larvae are devoid of staining (Figure 5a).”

In the paper

“For instance, miR-92b is downregulated in most mature neurons whereas, conversely, miR-124 is absent from proliferative cells and widely expressed in differentiated neurons.”

In the paper

“For instance, miR-34 shows conserved expression in the larval and adult hindbrain (Mauthner neuron, (MAC) and presumptive octavolateral area (OA) in Figure 5c; MAC and octavolateral nuclei (medial octavolateral (MON), anterior octaval (AON), magnocellular octaval (MaON) in Figure 5d) but also expands to include forebrain and midbrain cells of the habenulae (Had in Figure 5f), posterior tuberculum”

In the paper

“However, there are sharp transitions between domains of expression and non-expression, with some structures, such as the habenular nuclei, devoid of expression.”

In the paper

“miR-100 also shows robust habenular expression (Figure K in Additional data file 25) while miR-92b and miR-34b are expressed in ventricular cells adjacent to the mature habenular nuclei (Figure J in Additional data file 6, and Figure L in Additional data file 25).”

In the paper

“It reveals a wide diversity in miRNA expression, ranging from single cell types to the majority of CNS cells and from transient to constitutive expression.”

In the paper

“A few of the miRNAs we examined show expression restricted to very few cells and usually expressing cells share some characteristics of function and/or form.”

In the paper

“As described above, miR-222 expression is also largely conserved between larvae and adults (Figure 3h-l) but de novo expression in the adult facial and vagal lobes is also observed (LVII, LX, Figure I in Additional data file 20).”

In the paper

“We observe that in the case of let-7a, miR-92b and miR-153a, one mismatch strongly reduces the hybridization signal. Since there is still some staining left, we cannot exclude some cross-hybridization with other members of the respective miRNA families.”

In the paper

“Although expression of mouse miR-375 in the pituitary has not been ascertained, it is expressed in pancreatic beta cells [45] and appears to function in the regulation of insulin secretion.”

What the sources say

• ?Not checked — no full text of the sourcecites [45] Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, et al: A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004, 432: 226-230. 10.1038/nature03076. source

In the paper

“In a similar manner, other miRNAs belonging to a particular cluster seem to largely share expression patterns but also have subtle differences in transcript localization.”

In the paper

“miR-181a and miR-181b belong to the same family but differ in three nucleotides outside the seed region, suggesting that LNA probes can discriminate between their transcript expression profiles (Tables K and L in Additional data file 28, and Additional data file 29).”

In the paper

“This difference in expression may again be due to genomic duplication of the miRNAs.”

In the paper

“It is not obvious why there should be differences in miR-222 and miR-221 expression as they are present in the same cluster and one would predict that they are co-transcribed.”

In the paper

“miR-137 is expressed in the adult midbrain DTN (Figure 3g) and given the good correspondence of localized tegmental expression between 5 dpf and adult brains, we suggest that the cells in the larval tegmentum correspond to the presumptive midbrain DTN (Figure 3e,g; for other nuclei, see Additional data file 10, and Tables C and H in Additional data file 27).”

In the paper

“Together these results show that miRNA expression is frequently region or nucleus specific and can vary in the levels of expression from one group of cells to another.”

In the paper

“The acetylation step in the in situ hybridization was often omitted since it did not change or improve signal.”

In the paper

“As the silencing of loci is generally efficient, one might conclude that for most of the time in most mature neurons, some miRNAs are doing very little indeed, consistent with the idea that miRNAs confer robustness to programs of gene expression [11,12].”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB, Bartel DP: The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science. 2005, 310: 1817-1821. 10.1126/science.1121158. source
• ?Not checked — no full text of the sourcecites [12] Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM: Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005, 123: 1133-1146. 10.1016/j.cell.2005.11.023. source

In the paper

“There are well-described mechanisms for repressing and silencing loci (for example, [54]), but the absolute efficacy of such mechanisms is unknown.”

What the sources say

• ?Not checked — no full text of the sourcecites [54] Talbert PB, Henikoff S: Spreading of silent chromatin: inaction at a distance. Nat Rev Genet. 2006, 7: 793-803. 10.1038/nrg1920. source

In the paper

“Additional data file 28 includes Tables J-L, listing the miRNAs analyzed, the family/cluster they belong to and the mismatch LNA probe sequences used to test specificity of corresponding fully matching LNA probes.”

In the paper

“miRNAs that are induced when cells transition from one state to another are likely to target mRNAs that are expressed during the initial state and not required during the second state.”

In the paper

“These differences between larva and adult brain suggest downregulation of expression in most cells in the adult brain and either conserved or de novo expression in a few discrete cell populations (Additional data file 18, Tables B and G in Additional data file 27).”

In the paper

“Penetration of all reagents even in adult brains was generally very good, although in some preparations deep tissue in the brain did not label well and readers should be cautious about interpretation regarding absence of expression in such cases.”

In the paper

“For instance, miR-134 transcripts are localized to the dendritic compartments in which they function and miRNA activity is spatially/temporally regulated by extracellular signals [29].”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME: A brain-specific microRNA regulates dendritic spine development. Nature. 2006, 439: 283-289. 10.1038/nature04367. source

In the paper

“The mutual exclusion of miRNAs and their targets may be in either space or in time.”

In the paper

“A common feature of miRNA function is one of mutually exclusive expression of miRNAs and their target mRNAs [11,12].”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB, Bartel DP: The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science. 2005, 310: 1817-1821. 10.1126/science.1121158. source
• ?Not checked — no full text of the sourcecites [12] Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM: Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005, 123: 1133-1146. 10.1016/j.cell.2005.11.023. source

In the paper

“For instance, in zebrafish, miR-430 targets a large number of maternally deposited transcripts at the onset of zygotic transcription [6] and many examples of spatially exclusive expression domains of miRNAs and their targets have been documented (for example, [12,53]).”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K, Enright AJ, Schier AF: Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science. 2006, 312: 75-79. 10.1126/science.1122689. source

In the paper

“mRNAs from genes required for general cellular machinery are protected from miRNA action through possession of short 3' UTRs that are poor miRNA targets and genes required for specific cellular functions of the specific cell type are often miRNA anti-targets - that is, their 3' UTRs lack sequences that would enable binding of co-expressed miRNAs [12].”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM: Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005, 123: 1133-1146. 10.1016/j.cell.2005.11.023. source

In the paper

“The first is to function in neural stem cells/progenitors and the second is to facilitate the clearance of target mRNAs at spatial or temporal transitions.”

In the paper

“However, miR-134 is localized to dendrites and appears to modulate the levels of activity of a kinase that influences dendrite morphogenesis [29].”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME: A brain-specific microRNA regulates dendritic spine development. Nature. 2006, 439: 283-289. 10.1038/nature04367. source

In the paper

“Major changes in the transcriptome that occur when cells transition between states are thought to be brought about by transcriptional mechanisms independent of miRNA function and so it seems likely that many target mRNAs will not be actively transcribed once a transition has occurred (for example, [6]).”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K, Enright AJ, Schier AF: Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science. 2006, 312: 75-79. 10.1126/science.1122689. source

In the paper

“This analysis of habenular miRNA profiles illustrates that specific brain nuclei can express combinations of different miRNAs, some throughout life and some associated with differentiation.”

In the paper

“This profile is one of the best conserved miRNA patterns, as a similar restriction to mature neurons is seen for mouse and fly miR-124 [12,30].”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM: Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005, 123: 1133-1146. 10.1016/j.cell.2005.11.023. source
• ?Not checked — no full text of the sourcecites [30] Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG: Regulation of miRNA expression during neural cell specification. Eur J Neurosci. 2005, 21: 1469-1477. source

In the paper

“In such situations, the miRNA is expressed at high levels in comparison to the target mRNA and the expectation is that miRNA function is to maintain low levels of target gene activity.”

In the paper

“Neuroanatomical documentation of the zebrafish brain, particularly at larval stages, is far from complete and so our annotation is not always definitive.”