ArticleNeural development2015
Multi-site phosphorylation regulates NeuroD4 activity during primary neurogenesis: a conserved mechanism amongst proneural proteins.
Article in Neural development, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Article
- Neocortical neurogenesis: a proneural gene perspective.The FEBS journal · 2025Review
- Identifying the NEAT1/miR-26b-5p/S100A2 axis as a regulator in Parkinson's disease based on the ferroptosis-related genes.PloS one · 2024Article
- Ndst1, a heparan sulfate modification enzyme, regulates neuroectodermal patterning by enhancing Wnt signaling in Xenopus.Development, growth & differentiation · 2023Article
- Neurogenin 2 and Neuronal Differentiation 1 Control Proper Development of the Chick Trigeminal Ganglion and Its Nerve Branches.Journal of developmental biology · 2023Article
- Type one protein phosphatase regulates fixed-carbon starvation-induced autophagy in Arabidopsis.The Plant cell · 2022Article
- The Role of Neurod Genes in Brain Development, Function, and Disease.Frontiers in molecular neuroscience · 2021Article
- New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex.Frontiers in molecular neuroscience · 2021Review
- C3orf70 Is Involved in Neural and Neurobehavioral Development.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Multi-site phosphorylation controls the neurogenic and myogenic activity of E47.Biochemical and biophysical research communications · 2019Article
- N-terminal phosphorylation of xHes1 controls inhibition of primary neurogenesis in Xenopus.Biochemical and biophysical research communications · 2019Article
- The developmental origin of brain tumours: a cellular and molecular framework.Development (Cambridge, England) · 2018Review
- All in the family: proneural bHLH genes and neuronal diversity.Development (Cambridge, England) · 2018Review
- C8orf46 homolog encodes a novel protein Vexin that is required for neurogenesis in Xenopus laevis.Developmental biology · 2018Article
- Interaction between opposing modes of phospho-regulation of the proneural proteins Ascl1 and Ngn2.Wellcome open research · 2018Article
- The N terminus of Ascl1 underlies differing proneural activity of mouse andWellcome open research · 2018Article
- Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation.Developmental cell · 2017Article
- Article
- The Repression of Atoh1 by Neurogenin1 during Inner Ear Development.Frontiers in molecular neuroscience · 2017Article
- Signaling and Transcription Factors during Inner Ear Development: The Generation of Hair Cells and Otic Neurons.Frontiers in cell and developmental biology · 2017Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundBasic Helix Loop Helix (bHLH) proneural transcription factors are master regulators of neurogenesis that act at multiple stages in this process. We have previously demonstrated that multi-site phosphorylation of two members of the proneural protein family, Ngn2 and Ascl1, limits their ability to drive neuronal differentiation when cyclin-dependent kinase levels are high, as would be found in rapidly cycling cells. Here we investigate potential phospho-regulation of proneural protein NeuroD4 (also known as Xath3), the Xenopus homologue of Math3/NeuroM, that functions downstream of Ngn2 in the neurogenic cascade.
resultsUsing the developing Xenopus embryo system, we show that NeuroD4 is expressed and phosphorylated during primary neurogenesis, and this phosphorylation limits its ability to drive neuronal differentiation. Phosphorylation of up to six serine/threonine-proline sites contributes additively to regulation of NeuroD4 proneural activity without altering neuronal subtype specification, and number rather than location of available phospho-sites is the key for limiting NeuroD4 activity. Mechanistically, a phospho-mutant NeuroD4 displays increased protein stability and enhanced chromatin binding relative to wild-type NeuroD4, resulting in transcriptional up-regulation of a range of target genes that further promote neuronal differentiation.
conclusionsMulti-site phosphorylation on serine/threonine-proline pairs is a widely conserved mechanism of limiting proneural protein activity, where it is the number of phosphorylated sites, rather than their location that determines protein activity. Hence, multi-site phosphorylation is very well suited to allow co-ordination of proneural protein activity with the cellular proline-directed kinase environment.
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