ERK5 MAP kinase regulates neurogenin1 during cortical neurogenesis.
The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors.
Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.
Paige
P
Cundiff
Lidong
L
Liu
Yupeng
Y
Wang
Junhui
J
Zou
Yung-Wei
YW
Pan
Glen
G
Abel
Xin
X
Duan
Guo-Li
GL
Ming
Chris
C
Englund
Robert
R
Hevner
Zhengui
Z
Xia
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D007381:Intermediate Filament Proteins; D048054:Mitogen-Activated Protein Kinase 7; D009419:Nerve Tissue Proteins; D064231:Nestin; D011993:Recombinant Fusion Proteins; C577484:NES protein, human; C577486:Nes protein, rat; C510879:neurogenin-1, rat