The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development

Sabrina Pfurr, Yu Hsuan Chu, Christian Bohrer, Franziska Greulich, Robert Beattie, Könül Mammadzada, Miriam Hils, Sebastian J. Arnold, Verdon Taylor, Kristina Schachtrup, N. Henriette Uhlenhaut, Christian Schachtrup

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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).

Original languageEnglish
Pages (from-to)3917-3931
Number of pages15
JournalDevelopment (Cambridge)
Volume144
Issue number21
DOIs
StatePublished - 1 Nov 2017
Externally publishedYes

Keywords

  • Basic helix-loop-helix transcription factor
  • Cell cycle regulation
  • Cortical neurogenesis
  • E2A
  • Enhancer
  • Neurite outgrowth
  • P57(KIP2)

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