Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain

Sato, T., Sato, F., Kamezaki, A., Sakaguchi, K., Tanigome, R., Kawakami, K., Sehara-Fujisawa, A.
PLoS One   10: e0127360 (Journal)
Registered Authors
Kawakami, Koichi, Sato, Tomomi
MeSH Terms
  • Animals
  • Brain/cytology
  • Brain/drug effects
  • Brain/metabolism*
  • Cell Division/drug effects
  • Cell Division/physiology*
  • Gene Expression Regulation, Developmental
  • Neural Stem Cells/cytology
  • Neural Stem Cells/drug effects
  • Neural Stem Cells/metabolism*
  • Neuregulin-1/metabolism*
  • Neurogenesis/drug effects
  • Neurogenesis/physiology*
  • Neurons/cytology
  • Neurons/drug effects
  • Neurons/metabolism*
  • Quinazolines/pharmacology
  • Signal Transduction/drug effects
  • Signal Transduction/physiology
  • Tyrphostins/pharmacology
  • Zebrafish
26001123 Full text @ PLoS One
Post-mitotic neurons are generated from neural progenitor cells (NPCs) at the expense of their proliferation. Molecular and cellular mechanisms that regulate neuron production temporally and spatially should impact on the size and shape of the brain. While transcription factors such as neurogenin1 (neurog1) and neurod govern progression of neurogenesis as cell-intrinsic mechanisms, recent studies show regulatory roles of several cell-extrinsic or intercellular signaling molecules including Notch, FGF and Wnt in production of neurons/neural progenitor cells from neural stem cells/radial glial cells (NSCs/RGCs) in the ventricular zone (VZ). However, it remains elusive how production of post-mitotic neurons from neural progenitor cells is regulated in the sub-ventricular zone (SVZ). Here we show that newborn neurons accumulate in the basal-to-apical direction in the optic tectum (OT) of zebrafish embryos. While neural progenitor cells are amplified by mitoses in the apical ventricular zone, neurons are exclusively produced through mitoses of neural progenitor cells in the sub-basal zone, later in the sub-ventricular zone, and accumulate apically onto older neurons. This neurogenesis depends on Neuregulin 1 type II (NRG1-II)-ErbB signaling. Treatment with an ErbB inhibitor, AG1478 impairs mitoses in the sub-ventricular zone of the optic tectum. Removal of AG1478 resumes sub-ventricular mitoses without precedent mitoses in the apical ventricular zone prior to basal-to-apical accumulation of neurons, suggesting critical roles of ErbB signaling in mitoses for post-mitotic neuron production. Knockdown of NRG1-II impairs both mitoses in the sub-basal/sub-ventricular zone and the ventricular zone. Injection of soluble human NRG1 into the developing brain ameliorates neurogenesis of NRG1-II-knockdown embryos, suggesting a conserved role of NRG1 as a cell-extrinsic signal. From these results, we propose that NRG1-ErbB signaling stimulates cell divisions generating neurons from neural progenitor cells in the developing vertebrate brain.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes