Molecular Control of Neurogenesis: A View from the Mammalian Cerebral Cortex

Martynoga, Ben; Drechsel, Daniela; Guillemot, François

doi:10.1101/cshperspect.a008359

Cited by 168 publications

(185 citation statements)

References 136 publications

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“…The ability of neural stem or progenitor cells (NSCs) to produce different types of neurons is determined by intrinsic genetic programs (Martynoga et al, 2012;Miyata et al, 2010;Shen et al, 2006). Cell fate can also be specified by signals from the local environment in the nervous system (Borello and Pierani, 2010;Guillemot and Zimmer, 2011).…”

Section: Introductionmentioning

confidence: 99%

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

Xu¹,

Xiao²,

Jakovčevski³

et al. 2014

Development

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Abnormal generation of inhibitory neurons that synthesize c-aminobutyric acid (GABAergic) is characteristic of neuropsychological disorders. We provide evidence that the extracellular matrix molecule tenascin-R (TNR) -which is predominantly expressed by a subpopulation of interneuronsplays a role in the generation of GABAergic and granule neurons in the murine dentate gyrus by regulating fate determination of neural stem or progenitor cells (NSCs). During development, absence of TNR in constitutively TNR-deficient (TNR 2/2 ) mice results in increased numbers of dentate gyrus GABAergic neurons, decreased expression of its receptor b1 integrin, increased activation of p38 MAPK and increased expression of the GABAergic specification gene Ascl1. Postnatally, increased GABAergic input to adult hippocampal NSCs in TNR 2/2 mice is associated not only with increased numbers of GABAergic and, particularly, parvalbumin-immunoreactive neurons, as seen during development, but also with increased numbers of granule neurons, thus contributing to the increased differentiation of NSCs into granule cells. These findings indicate the importance of TNR in the regulation of hippocampal neurogenesis and suggest that TNR acts through distinct direct and indirect mechanisms during development and in the adult.

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Section: Introductionmentioning

confidence: 99%

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

Xu¹,

Xiao²,

Jakovčevski³

et al. 2014

Development

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“…1,2 Precise regulation of the balance between the undifferentiated progenitor state and neuronal differentiation in the embryonic neocortex is essential for the correct development of the adult cerebral cortex, but the mechanisms regulating the progenitor-to-neuron transition in this brain region remain incompletely characterized.…”

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confidence: 99%

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

et al. 2013

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The Groucho/transducin-like Enhancer of split 1 (Gro/TLE1):Hes1 transcriptional repression complex acts in cerebral cortical neural progenitor cells to inhibit neuronal differentiation. The molecular mechanisms that regulate the anti-neurogenic function of the Gro/TLE1:Hes1 complex during cortical neurogenesis remain to be defined. Here we show that prolyl isomerase Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and homeodomain-interacting protein kinase 2 (HIPK2) are expressed in cortical neural progenitor cells and form a complex that interacts with the Gro/TLE1:Hes1 complex. This association depends on the enzymatic activities of both HIPK2 and Pin1, as well as on the association of Gro/TLE1 with Hes1, but is independent of the previously described Hes1-activated phosphorylation of Gro/TLE1. Interaction with the Pin1:HIPK2 complex results in Gro/TLE1 hyperphosphorylation and weakens both the transcriptional repression activity and the anti-neurogenic function of the Gro/ TLE1:Hes1 complex. These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation. Cell Death and Differentiation (2014) 21, 321-332; doi:10.1038/cdd.2013.160; published online 22 November 2013During mammalian brain development, the ventricular zone of the dorsolateral region of the alar telencephalon (neocortex) contains undifferentiated neural progenitor cells that initially undergo symmetric (proliferative) divisions to generate two new progenitor cells and later undergo asymmetric (differentiative) divisions to give rise to a new mitotic progenitor and a post-mitotic neuron.

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“…The development of the cerebral cortex involves complex steps, requiring tightly regulated molecular mechanisms for the efficient and precise control of gene expression 1. Some of the molecular pathways that control gene expression are mediated by microRNAs, a class of noncoding RNAs that regulate gene expression at the posttranscriptional level 2.…”

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confidence: 99%

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Avansini

Torres

Vieira

et al. 2018

Annals of Neurology

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ObjectiveFocal cortical dysplasias (FCDs) are an important cause of drug‐resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.MethodsWe used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.Resultshsa‐let‐7f (p = 0.039), hsa‐miR‐31 (p = 0.0078), and hsa‐miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2‐target, is upregulated (p < 0.001). In vitro experiments showed that hsa‐miR‐34a downregulates NEUROG2 by binding to its 5′‐untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway.InterpretationOur findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa‐miR‐34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623–635

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Molecular Control of Neurogenesis: A View from the Mammalian Cerebral Cortex

Cited by 168 publications

References 136 publications

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

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