Neurod1 is essential for the survival and maturation of adult-born neurons

Gao, Zhengliang; Ure, Kerstin; Ables, Jessica L.; Lagace, Diane C.; Nave, Klaus Armin; Goebbels, Sandra; Eisch, Amelia J.; Hsieh, Jenny

doi:10.1038/nn.2385

Cited by 408 publications

(397 citation statements)

References 12 publications

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“…[60] and the present study) and (b) there is no overlap between the expression of Sox2 and Neurod1 in the DG (refs. [61,62] and our unpublished observations), the lower LI of Neurod1 þ cells when compared with Neurod1 À cells suggests that immature actively proliferating precursors (type 2a) cycle more rapidly than do neuronally committed precursors (types 2b and 3), supporting for the first time the ''cell cycle length hypothesis'' for adult neurogenic niches. Moreover, the lengthening of G 1 observed in the absence of (F-I).…”

Section: Discussionmentioning

confidence: 51%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 51%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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“…Characterization of iPSC-derived NSCs/eNPCs and neurons Western blotting analysis of NSCs/eNPCs showed a relatively low expression level of NeuroD1, indicating the absence of, or the presence of only a minor fraction of late NPCs 25 (Fig. 4a).…”

Section: Outline Of Differentiation Protocol and Nomenclaturementioning

confidence: 99%

Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation

et al. 2014

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Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented opportunity to perform highthroughput screening of novel drugs for neurological and neurodegenerative diseases. Such screenings require a robust and scalable method for generating large numbers of mature, differentiated neuronal cells. Currently available methods based on differentiation of embryoid bodies (EBs) or directed differentiation of adherent culture systems are either expensive or are not scalable. We developed a protocol for large-scale generation of neuronal stem cells (NSCs)/early neural progenitor cells (eNPCs) and their differentiation into neurons. Our scalable protocol allows robust and cost-effective generation of NSCs/eNPCs from iPSCs. Following culture in neurobasal medium supplemented with B27 and BDNF, NSCs/ eNPCs differentiate predominantly into vesicular glutamate transporter 1 (VGLUT1) positive neurons. Targeted mass spectrometry analysis demonstrates that iPSC-derived neurons express ligand-gated channels and other synaptic proteins and whole-cell patch-clamp experiments indicate that these channels are functional. The robust and cost-effective differentiation protocol described here for large-scale generation of NSCs/eNPCs and their differentiation into neurons paves the way for automated high-throughput screening of drugs for neurological and neurodegenerative diseases.

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“…One of the key molecules expressed by local astrocytes within the neurogenic niche of the adult hippocampus is Wnt3, which is required for the generation of new granule cells (7,32). Supporting the critical role of Wnt signaling in adult neurogenesis, it has been recently shown that NeuroD1, a basic helix- loop-helix transcription factor required for granule cell and olfactory neuron generation in the embryonic and adult brain, is regulated by β-catenin (11,12). We now show that Prox1, expressed in newborn but also mature granule cells selectively in the DG, is a downstream target of β-catenin-TCF/LEF signaling in the context of neurogenesis and is required for the proper differentiation and survival of newborn granule cells but not for the maintenance of granule cells after they have fully matured.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that NeuroD1, a basic helix-loop-helix transcription factor required for granule cell genesis in the embryonic and adult DG, is regulated by β-catenin-dependent signaling (9)(10)(11)(12). However, NeuroD1 is not only important for hippocampal neurogenesis but is also involved in the generation of SVZ-derived olfactory neurons (11,13,14). Thus, the network of genes regulated by the Wnt pathway to selectively generate DG granule cells in the adult hippocampus remains unknown.…”

mentioning

confidence: 99%

Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis

Karalay

Doberauer

Vadodaria

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

174

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Neural stem cells (NSCs) generate new granule cells throughout life in the mammalian hippocampus. Canonical Wnt signaling regulates the differentiation of NSCs towards the neuronal lineage. Here we identified the prospero-related homeodomain transcription factor Prox1 as a target of β-catenin–TCF/LEF signaling in vitro and in vivo. Prox1 overexpression enhanced neuronal differentiation whereas shRNA-mediated knockdown of Prox1 impaired the generation of neurons in vitro and within the hippocampal niche. In contrast, Prox1 was not required for survival of adult-generated granule cells after they had matured, suggesting a role for Prox1 in initial granule cell differentiation but not in the maintenance of mature granule cells. The data presented here characterize a molecular pathway from Wnt signaling to a transcriptional target leading to granule cell differentiation within the adult brain and identify a stage-specific function for Prox1 in the process of adult neurogenesis.

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Neurod1 is essential for the survival and maturation of adult-born neurons

Cited by 408 publications

References 12 publications

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation

Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis

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