Neurogenin Promotes Neurogenesis and Inhibits Glial Differentiation by Independent Mechanisms

Sun, Yi; Nadal-Vicens, Mireya; Misono, Stephanie; Lin, Michael Z.; Zubiaga, Ana M.; Hua, Xianxing; Fan, Guoping; Greenberg, Michael E.

doi:10.1016/s0092-8674(01)00224-0

Cited by 729 publications

(642 citation statements)

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“…CBP/p300 complexes with the transcription factor neurogenin 2 and the retinoic acid receptor to induce histone acetylation and transcriptionally active chromatin during motor neuron specification [52]. The closely related basic helix-loophelix (bHLH) factor neurogenin 1 (Ngn1) represses gliogenesis through the sequestration of the CBP-Smad1 complex away from astrocyte differentiation genes, such as glial fibrillary acidic protein (GFAP), during neurogenesis [53]. CBP/p300 and Smad1, separately or together, subsequently associate with neurogenin at neural-specific promoters, such as NeuroD, thereby promoting neuronal differentiation [53].…”

Section: Hats During Neural Developmentmentioning

confidence: 99%

“…The closely related basic helix-loophelix (bHLH) factor neurogenin 1 (Ngn1) represses gliogenesis through the sequestration of the CBP-Smad1 complex away from astrocyte differentiation genes, such as glial fibrillary acidic protein (GFAP), during neurogenesis [53]. CBP/p300 and Smad1, separately or together, subsequently associate with neurogenin at neural-specific promoters, such as NeuroD, thereby promoting neuronal differentiation [53]. The posttranslational modifications of CBP and p300 also regulate the functions of these enzymes, and the phosphorylation of CBP through the atypical protein kinase C (aPKCζ) plays a critical role in controlling glial and neuronal differentiation [54].…”

Section: Hats During Neural Developmentmentioning

confidence: 99%

“…Increased expression of neurogenin (Ngn1) titrates this complex, thus leading to the release of STAT, blocking GFAP expression. The new Ngn1-CBP/p300-SMAD complex subsequently binds to the E box elements, which results in a neuron cell type due to the activation of NeuroD1 expression [53]. CBP/ p300 when bound to retinoic acid receptor (RAR) and neurogenin 2 (Ngn2) leads to a differentiation of the motor neuron cells.…”

Section: Druggability Of Hat Domainsmentioning

confidence: 99%

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Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Section: Hats During Neural Developmentmentioning

confidence: 99%

Section: Hats During Neural Developmentmentioning

confidence: 99%

Section: Druggability Of Hat Domainsmentioning

confidence: 99%

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Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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“…During brain development, NEUROG2 has a specific spatiotemporal expression pattern, because it is exclusively detected in the ventricular zone and only during neurogenesis (Fig 5A) 25. It has been demonstrated that a negative feedback mechanism is essential for the correct transition between the inhibition of neurogenesis and the induction of early gliogenesis 26.…”

Section: Discussionmentioning

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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“…The basic helix-loop-helix (bHLH) transcriptional factors play a major part in this process [2,3], and they can be classified into three types according to their functions [4,5]. Class I, E proteins, including two isoforms of E2A gene product, E12 and E47, are ubiquitously expressed in all tissues and are capable of forming heterodimers with other bHLH proteins [6]; Class II, tissue-specific activators, are involved in cell fate determination, and bind DNA by forming heterodimers with E proteins [7,8]; Class III, negative regulators such as the Id and Hes families, inhibits the Class II bHLH protein activity by interfering with their functional dimerization [9][10][11].…”

Section: Introductionmentioning

confidence: 99%