title: Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain.
abstract: 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.
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan; Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Aosa
authors.initials: A
authors.lastname: Kamezaki
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Tanigome
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima-shi, Shizuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sehara-Fujisawa
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D020890:Neuregulin-1; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors