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Cited by 5MicroRNA in disease regulationNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

The Transcription Factor, α1ACT, Acts Through a MicroRNA Network to Regulate Neurogenesis and Cell Death During Neonatal Cerebellar Development

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Wei, Cenfu, Benzow, Kellie, Koob, Michael D., Gomez, Christopher M., Du, Xiaofei·2022·The Cerebellum
DOI 10.1007/s12311-022-01431-2PMC PMC10307715
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Abstract

MicroRNAs, a class of small RNA regulators, function throughout neurodevelopment, from neural stem cell neurogenesis to neuronal maturation, synaptic formation, and plasticity. α1ACT, a transcription factor (TF), plays a critical role in neonatal cerebellar development by regulating an ensemble of genes. Of these, ChIP-seq analysis matched near 50% genes directly regulated by α1ACT. Yet, more than half the regulated transcripts lacked direct interaction with α1ACT. To investigate whether α1ACT acts through a microRNA network, we studied α1ACT-associated simultaneous miRNA:mRNA transcriptome profiles, using miRNA-seq paired with RNA-seq. Thirty-one differentially expressed miRNAs (DEMs) associated with α1ACT-regulated differentially expressed genes (DEGs) were profiled in α1ACT-overexpressing PC12 cells and were further validated in neonatal transgenic mouse cerebellum overexpressing α1ACT in a context-dependent manner. Here, we also demonstrated that α1ACT facilitates neurogenesis and development of dendritic synapses and is partially a result of the downregulation of the miR-99 cluster, miR-143, miR-23, miR-146, miR-363, and miR-484. On the other hand, the miR-181, miR-125, and miR-708 clusters were upregulated by α1ACT, which inhibit MAPK signaling and cell death pathways by targeting Ask1, Odc1, Atf4, and Nuf2 for decreased expression. MiR-181a-5p was verified as the most abundant DEM in neonatal cerebellum, which was further induced by α1ACT. Overall, under α1ACT modulation, up-/downregulated miRNA clusters with their paired target genes may form a regulatory network controlling the balance between the neuronal proliferation, differentiation, and cell death in the cerebellum to promote neonatal development. Our findings concerning the α1ACT-related miRNA/mRNA expression profiles in neonatal cerebellum may inform future investigations for cerebellar development.

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  • Levels of miR-23 declined in the cerebellum of transgenic mice with α1ACT overexpression, confirming its function on neurogenesis and development promotion of dendritic synapses via MAPK signaling and cell death pathways, and controls the balance between cerebellar neuronal proliferation, differentiation, and cell death.

    “the levels of miR-23 declined in the cerebellum of transgenic mice with α1ACT overexpression, confirming its function on the neurogenesis and development promotion of dendritic synapses via MAPK signaling and cell death pathways, and controls the balance between cerebellar neuronal proliferation, differentiation, and cell death [132].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [132]

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References 67 · Cited by 5

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  1. [1]Rahimi-Balaei M Neuronal migration during development of the cerebellum Front Cell Neurosci 2018 12 484 10.3389/fncel.2018.00484 30618631 PMC6304365 · DOI
  2. [2]Consalez GG Origins, development, and compartmentation of the granule cells of the cerebellum Front Neural Circuits 2020 14 611841 10.3389/fncir.2020.611841 33519389 PMC7843939 · DOI
  3. [3]Ming GL Song H Adult neurogenesis in the mammalian brain: significant answers and significant questions Neuron 2011 70 4 687 702 10.1016/j.neuron.2011.05.001 21609825 PMC3106107 · DOI · Paper page
  4. [4]Wechsler-Reya RJ Scott MP Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog Neuron 1999 22 1 103 114 10.1016/S0896-6273(00)80682-0 10027293 · DOI
  5. [5]Kenney AM Cole MD Rowitch DH Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors Development 2003 130 1 15 28 10.1242/dev.00182 12441288 · DOI
  6. [6]Knoepfler PS Cheng PF Eisenman RN N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation Genes Dev 2002 16 20 2699 2712 10.1101/gad.1021202 12381668 PMC187459 · DOI
  7. [7]Ahlenius H Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain J Neurosci 2009 29 14 4408 4419 10.1523/JNEUROSCI.6003-08.2009 19357268 PMC6665731 · DOI
  8. [8]Krichevsky AM Specific microRNAs modulate embryonic stem cell-derived neurogenesis Stem Cells 2006 24 4 857 864 10.1634/stemcells.2005-0441 16357340 PMC2605651 · DOI · Paper page
  9. [9]Miska EA Microarray analysis of microRNA expression in the developing mammalian brain Genome Biol 2004 5 9 R68 10.1186/gb-2004-5-9-r68 15345052 PMC522875 · DOI · Paper page
  10. [11]Davis GM Haas MA Pocock R MicroRNAs: not "fine-tuners" but key regulators of neuronal development and function Front Neurol 2015 6 245 10.3389/fneur.2015.00245 26635721 PMC4656843 · DOI
  11. [12]Du X alpha1ACT is essential for survival and early cerebellar programming in a critical neonatal window Neuron 2019 102 4 770 785 e7 10.1016/j.neuron.2019.02.036 30922876 PMC6533132 · DOI
  12. [13]Goldowitz D Hamre K The cells and molecules that make a cerebellum Trends Neurosci 1998 21 9 375 382 10.1016/S0166-2236(98)01313-7 9735945 · DOI
  13. [14]Butts T Green MJ Wingate RJ Development of the cerebellum: simple steps to make a 'little brain' Development 2014 141 21 4031 4041 10.1242/dev.106559 25336734 · DOI · Paper page
  14. [15]Zamore PD Haley B Ribo-gnome: the big world of small RNAs Science 2005 309 5740 1519 1524 10.1126/science.1111444 16141061 · DOI
  15. [16]Shyu AB Wilkinson MF van Hoof A Messenger RNA regulation: to translate or to degrade EMBO J 2008 27 3 471 481 10.1038/sj.emboj.7601977 18256698 PMC2241649 · DOI
  16. [17]Motti D Bixby JL Lemmon VP MicroRNAs and neuronal development Semin Fetal Neonatal Med 2012 17 6 347 352 10.1016/j.siny.2012.07.008 22906916 PMC3490020 · DOI
  17. [18]O'Carroll D Schaefer A General principals of miRNA biogenesis and regulation in the brain Neuropsychopharmacology 2013 38 1 39 54 10.1038/npp.2012.87 22669168 PMC3521995 · DOI · Paper page
  18. [19]Stefani G Slack FJ Small non-coding RNAs in animal development Nat Rev Mol Cell Biol 2008 9 3 219 230 10.1038/nrm2347 18270516 · DOI
  19. [20]Bicker S Schratt G microRNAs: tiny regulators of synapse function in development and disease J Cell Mol Med 2008 12 5A 1466 1476 10.1111/j.1582-4934.2008.00400.x 18624757 PMC3918062 · DOI
  20. [21]Du X Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6 Cell 2013 154 1 118 133 10.1016/j.cell.2013.05.059 23827678 PMC3939801 · DOI
  21. [22]Huang JC Using expression profiling data to identify human microRNA targets Nat Methods 2007 4 12 1045 1049 10.1038/nmeth1130 18026111 · DOI
  22. [23]Gamache J Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice Nat Commun 2019 10 1 2479 10.1038/s41467-019-10428-1 31171783 PMC6554306 · DOI
  23. [24]Greene LA Tischler AS Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor Proc Natl Acad Sci U S A 1976 73 7 2424 2428 10.1073/pnas.73.7.2424 1065897 PMC430592 · DOI
  24. [25]Greene LA Rein G Release, storage and uptake of catecholamines by a clonal cell line of nerve growth factor (NGF) responsive pheo-chromocytoma cells Brain Res 1977 129 2 247 263 10.1016/0006-8993(77)90005-1 560237 · DOI
  25. [26]Schubert D The modulation of neurotransmitter synthesis by steroid hormones and insulin Brain Res 1980 190 1 67 79 10.1016/0006-8993(80)91160-9 6103732 · DOI
  26. [27]Das KP Freudenrich TM Mundy WR Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures Neurotoxicol Teratol 2004 26 3 397 406 10.1016/j.ntt.2004.02.006 15113601 · DOI
  27. [28]Wiatrak B, et al. PC12 cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells. 2020;9(4). PMC7227003 32295099
  28. [29]Yin H Neurite outgrowth resistance to rho kinase inhibitors in PC12 Adh cell Cell Biol Int 2015 39 5 563 576 10.1002/cbin.10423 25571866 · DOI
  29. [30]Westerink RH Ewing AG The PC12 cell as model for neurosecretion Acta Physiol (Oxf) 2008 192 2 273 285 10.1111/j.1748-1716.2007.01805.x 18005394 PMC2663028 · DOI
  30. [31]Vitsios DM Enright AJ Chimira: analysis of small RNA sequencing data and microRNA modifications Bioinformatics 2015 31 20 3365 3367 10.1093/bioinformatics/btv380 26093149 PMC4595902 · DOI
  31. [32]Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011;39(Database issue):D152–7. PMC3013655 21037258
  32. [33]Aparicio-Puerta E sRNAbench and sRNAtoolbox 2019: intuitive fast small RNA profiling and differential expression Nucleic Acids Res 2019 47 W1 W530 W535 10.1093/nar/gkz415 31114926 PMC6602500 · DOI
  33. [34]Robinson MD McCarthy DJ Smyth GK edgeR: a bioconductor package for differential expression analysis of digital gene expression data Bioinformatics 2010 26 1 139 140 10.1093/bioinformatics/btp616 19910308 PMC2796818 · DOI · Paper page
  34. [35]Dweep H Gretz N miRWalk2.0: a comprehensive atlas of microRNA-target interactions Nat Methods 2015 12 8 697 10.1038/nmeth.3485 26226356 · DOI
  35. [36]Ge SX Jung D Yao R ShinyGO: a graphical gene-set enrichment tool for animals and plants Bioinformatics 2020 36 8 2628 2629 10.1093/bioinformatics/btz931 31882993 PMC7178415 · DOI · Paper page
  36. [37]Shannon P Cytoscape: a software environment for integrated models of biomolecular interaction networks Genome Res 2003 13 11 2498 2504 10.1101/gr.1239303 14597658 PMC403769 · DOI · Paper page
  37. [38]Altuvia Y Clustering and conservation patterns of human microRNAs Nucleic Acids Res 2005 33 8 2697 2706 10.1093/nar/gki567 15891114 PMC1110742 · DOI
  38. [39]Kabekkodu SP Clustered miRNAs and their role in biological functions and diseases Biol Rev Camb Philos Soc 2018 93 4 1955 1986 10.1111/brv.12428 29797774 · DOI
  39. [40]Meister G Tuschl T Mechanisms of gene silencing by double-stranded RNA Nature 2004 431 7006 343 349 10.1038/nature02873 15372041 · DOI
  40. [41]Orom UA Nielsen FC Lund AH MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation Mol Cell 2008 30 4 460 471 10.1016/j.molcel.2008.05.001 18498749 · DOI · Paper page
  41. [42]Tay Y MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation Nature 2008 455 7216 1124 1128 10.1038/nature07299 18806776 · DOI
  42. [43]Rajewsky N microRNA target predictions in animals Nat Genet 2006 38 Suppl S8 13 10.1038/ng1798 16736023 · DOI
  43. [45]Cherone JM Jorgji V Burge CB Cotargeting among microRNAs in the brain Genome Res 2019 29 11 1791 1804 10.1101/gr.249201.119 31649056 PMC6836737 · DOI · Paper page
  44. [46]Ichijo H Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways Science 1997 275 5296 90 94 10.1126/science.275.5296.90 8974401 · DOI
  45. [47]Takeda K Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells J Biol Chem 2000 275 13 9805 9813 10.1074/jbc.275.13.9805 10734135 · DOI
  46. [48]Kwon JE Kim EK Choi EJ Stabilization of the survival motor neuron protein by ASK1 FEBS Lett 2011 585 9 1287 1292 10.1016/j.febslet.2011.04.011 21496457 · DOI
  47. [49]Qing G ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation Cancer Cell 2012 22 5 631 644 10.1016/j.ccr.2012.09.021 23153536 PMC3510660 · DOI · Paper page
  48. [50]Fineberg SK Kosik KS Davidson BL MicroRNAs potentiate neural development Neuron 2009 64 3 303 309 10.1016/j.neuron.2009.10.020 19914179 · DOI
  49. [52]De Pietri Tonelli D miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex Development 2008 135 23 3911 3921 10.1242/dev.025080 18997113 PMC2798592 · DOI · Paper page
  50. [53]Schaefer A Cerebellar neurodegeneration in the absence of microRNAs J Exp Med 2007 204 7 1553 1558 10.1084/jem.20070823 17606634 PMC2118654 · DOI · Paper page
  51. [54]Fiore R Siegel G Schratt G MicroRNA function in neuronal development, plasticity and disease Biochim Biophys Acta 2008 1779 8 471 478 10.1016/j.bbagrm.2007.12.006 18194678 · DOI
  52. [55]Pucci B Kasten M Giordano A Cell cycle and apoptosis Neoplasia 2000 2 4 291 299 10.1038/sj.neo.7900101 11005563 PMC1550296 · DOI
  53. [56]Cerri S Cell proliferation and death in the brain of active and hibernating frogs J Anat 2009 215 2 124 131 10.1111/j.1469-7580.2009.01101.x 19531087 PMC2740959 · DOI
  54. [57]Lossi L Gambino G Apoptosis of the cerebellar neurons Histol Histopathol 2008 23 3 367 380 18072093
  55. [58]Marzban H Cellular commitment in the developing cerebellum Front Cell Neurosci 2014 8 450 25628535 PMC4290586
  56. [59]King KL Cidlowski JA Cell cycle and apoptosis: common pathways to life and death J Cell Biochem 1995 58 2 175 180 10.1002/jcb.240580206 7673325 · DOI
  57. [60]Krek A Combinatorial microRNA target predictions Nat Genet 2005 37 5 495 500 10.1038/ng1536 15806104 · DOI · Paper page
  58. [61]Lim LP Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs Nature 2005 433 7027 769 773 10.1038/nature03315 15685193 · DOI · Paper page
  59. [62]Tobiume K ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis EMBO Rep 2001 2 3 222 228 10.1093/embo-reports/kve046 11266364 PMC1083842 · DOI
  60. [63]Cheon SY Cho KJ Pathological role of apoptosis signal-regulating kinase 1 in human diseases and its potential as a therapeutic target for cognitive disorders J Mol Med (Berl) 2019 97 2 153 161 10.1007/s00109-018-01739-9 30617854 · DOI
  61. [64]Guo X ASK1 in neurodegeneration Adv Biol Regul 2017 66 63 71 10.1016/j.jbior.2017.08.003 28882588 · DOI
  62. [65]Song J Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer's disease Int J Mol Sci 2014 15 2 2119 2129 10.3390/ijms15022119 24481061 PMC3958840 · DOI
  63. [66]Galli R Neural stem cells: an overview Circ Res 2003 92 6 598 608 10.1161/01.RES.0000065580.02404.F4 12676811 · DOI

Authors
Wei, C., Benzow, K., Koob, M. D., Gomez, C. M., & Du, X.
Affiliations
  • University of Chicago (US)
  • University of Minnesota (US)
Corresponding author
  • Gomez, Christopher M.
  • Du, Xiaofei
ORCID
Venue
The Cerebellum
Publisher
Springer Science and Business Media LLC
Published
2022-06-22
Volume
22
Issue
4
Pages
651-662
ISSN
  • 1473-4222 (ISSN-L)
  • 1473-4230
DOI
10.1007/s12311-022-01431-2
PMC
PMC10307715
OpenAlex
W4283277103
Cited by
5
References
67
Citations by year
2026: 1 · 2025: 2 · 2024: 2
FWCI
0.42
Type
journal article
Language
en
Update notices
correction (2023-05-18)
Open access
Licence
Locations
  • The Cerebellum (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R35NS116868, R01NS082788, R21NS094872-01, R01NS094665)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
transcription factors, microRNA networks, neurogenesis, neuronal cell death, miR-181a-5p, miR-143, miR-146, miR-23, miR-363, miR-484, miR-125, miR-708, MAPK signaling, ASK1, ODC1, ATF4, NUF2, PC12 cells
MeSH terms
Animals, Cerebellum, Mice, Transgenic, RNA, Messenger, Transcription Factors, Gene Expression Profiling, MicroRNAs, Mice, Rats, Neurogenesis

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