Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

Tessa Walcher, Qing Xie, Jian Sun, Martin Irmler, Johannes Beckers, Timucin Öztürk, Dierk Niessing, Anastassia Stoykova, Ales Cvekl, Jovica Ninkovic, Magdalena Götz

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

To achieve adequate organ development and size, cell proliferation and differentiation have to be tightly regulated and coordinated. The transcription factor Pax6 regulates patterning, neurogenesis and proliferation in forebrain development. The molecular basis of this regulation is not well understood. As the bipartite DNA-binding paired domain of Pax6 regulates forebrain development, we examined mice with point mutations in its individual DNA-binding subdomains PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C). This revealed distinct roles in regulating proliferation in the developing cerebral cortex, with the PAI and RED subdomain mutations reducing and increasing, respectively, the number of mitoses. Conversely, neurogenesis was affected only by the PAI subdomain mutation, phenocopying the neurogenic defects observed in full Pax6 mutants. Genome-wide expression profiling identified molecularly discrete signatures of Pax6Leca4 and Pax6Leca2 mutations. Comparison to Pax6 targets identified by chromatin immunoprecipitation led to the identification and functional characterization of distinct DNA motifs in the promoters of target genes dysregulated in the Pax6Leca2 or Pax6Leca4 mutants, further supporting the distinct regulatory functions of the DNA-binding subdomains. Thus, Pax6 achieves its key roles in the developing forebrain by utilizing particular subdomains to coordinate patterning, neurogenesis and proliferation simultaneously.

Original languageEnglish (US)
Pages (from-to)1123-1136
Number of pages14
JournalDevelopment (Cambridge)
Volume140
Issue number5
DOIs
StatePublished - 2013

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Neurogenesis
Prosencephalon
Dissection
Mutation
DNA
Nucleotide Motifs
Organ Size
Chromatin Immunoprecipitation
Point Mutation
Mitosis
Cerebral Cortex
Cell Differentiation
Transcription Factors
Cell Proliferation
Genome
Genes

Keywords

  • Cortex development
  • Mouse
  • Radial glia
  • Transcriptional regulator

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation. / Walcher, Tessa; Xie, Qing; Sun, Jian; Irmler, Martin; Beckers, Johannes; Öztürk, Timucin; Niessing, Dierk; Stoykova, Anastassia; Cvekl, Ales; Ninkovic, Jovica; Götz, Magdalena.

In: Development (Cambridge), Vol. 140, No. 5, 2013, p. 1123-1136.

Research output: Contribution to journalArticle

Walcher, T, Xie, Q, Sun, J, Irmler, M, Beckers, J, Öztürk, T, Niessing, D, Stoykova, A, Cvekl, A, Ninkovic, J & Götz, M 2013, 'Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation', Development (Cambridge), vol. 140, no. 5, pp. 1123-1136. https://doi.org/10.1242/dev.082875
Walcher, Tessa ; Xie, Qing ; Sun, Jian ; Irmler, Martin ; Beckers, Johannes ; Öztürk, Timucin ; Niessing, Dierk ; Stoykova, Anastassia ; Cvekl, Ales ; Ninkovic, Jovica ; Götz, Magdalena. / Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation. In: Development (Cambridge). 2013 ; Vol. 140, No. 5. pp. 1123-1136.
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