TY - JOUR
T1 - The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development
AU - Pfurr, Sabrina
AU - Chu, Yu Hsuan
AU - Bohrer, Christian
AU - Greulich, Franziska
AU - Beattie, Robert
AU - Mammadzada, Könül
AU - Hils, Miriam
AU - Arnold, Sebastian J.
AU - Taylor, Verdon
AU - Schachtrup, Kristina
AU - Henriette Uhlenhaut, N.
AU - Schachtrup, Christian
N1 - Publisher Copyright:
© 2017. Published by The Company of Biologists Ltd.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - During corticogenesis, distinct classes of neurons are born from progenitor cells located in the ventricular and subventricular zones, from where they migrate towards the pial surface to assemble into highly organized layer-specific circuits. However, the precise and coordinated transcriptional network activity defining neuronal identity is still not understood. Here, we show that genetic depletion of the basic helix-loop-helix (bHLH) transcription factor E2A splice variant E47 increased the number of Tbr1-positive deep layer and Satb2-positive upper layer neurons at E14.5, while depletion of the alternatively spliced E12 variant did not affect layer-specific neurogenesis. While ChIP-Seq identified a big overlap for E12-and E47-specific binding sites in embryonic NSCs, including sites at the cyclin-dependent kinase inhibitor (CDKI) Cdkn1c gene locus, RNASeq revealed a unique transcriptional regulation by each splice variant. E47 activated the expression of the CDKI Cdkn1c through binding to a distal enhancer. Finally, overexpression of E47 in embryonic NSCs in vitro impaired neurite outgrowth, and overexpression of E47 in vivo by in utero electroporation disturbed proper layer-specific neurogenesis and upregulated p57(KIP2) expression. Overall, this study identifies E2A target genes in embryonic NSCs and demonstrates that E47 regulates neuronal differentiation via p57(KIP2).
AB - During corticogenesis, distinct classes of neurons are born from progenitor cells located in the ventricular and subventricular zones, from where they migrate towards the pial surface to assemble into highly organized layer-specific circuits. However, the precise and coordinated transcriptional network activity defining neuronal identity is still not understood. Here, we show that genetic depletion of the basic helix-loop-helix (bHLH) transcription factor E2A splice variant E47 increased the number of Tbr1-positive deep layer and Satb2-positive upper layer neurons at E14.5, while depletion of the alternatively spliced E12 variant did not affect layer-specific neurogenesis. While ChIP-Seq identified a big overlap for E12-and E47-specific binding sites in embryonic NSCs, including sites at the cyclin-dependent kinase inhibitor (CDKI) Cdkn1c gene locus, RNASeq revealed a unique transcriptional regulation by each splice variant. E47 activated the expression of the CDKI Cdkn1c through binding to a distal enhancer. Finally, overexpression of E47 in embryonic NSCs in vitro impaired neurite outgrowth, and overexpression of E47 in vivo by in utero electroporation disturbed proper layer-specific neurogenesis and upregulated p57(KIP2) expression. Overall, this study identifies E2A target genes in embryonic NSCs and demonstrates that E47 regulates neuronal differentiation via p57(KIP2).
KW - Basic helix-loop-helix transcription factor
KW - Cell cycle regulation
KW - Cortical neurogenesis
KW - E2A
KW - Enhancer
KW - Neurite outgrowth
KW - P57(KIP2)
UR - http://www.scopus.com/inward/record.url?scp=85032785926&partnerID=8YFLogxK
U2 - 10.1242/dev.145698
DO - 10.1242/dev.145698
M3 - Article
C2 - 28939666
AN - SCOPUS:85032785926
SN - 0950-1991
VL - 144
SP - 3917
EP - 3931
JO - Development (Cambridge)
JF - Development (Cambridge)
IS - 21
ER -