title: Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation.
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 (Pax6(Leca4), N50K) and RED (Pax6(Leca2), 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 Pax6(Leca4) and Pax6(Leca2) 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 Pax6(Leca2) or Pax6(Leca4) 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.
authors: Institute of Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg-Munich, Germany.
authors: Tessa
authors: T
authors: Walcher
authors: Qing
authors: Q
authors: Xie
authors: Jian
authors: J
authors: Sun
authors: Martin
authors: M
authors: Irmler
authors: Johannes
authors: J
authors: Beckers
authors: Timucin
authors: T
authors: Öztürk
authors: Dierk
authors: D
authors: Niessing
authors: Anastassia
authors: A
authors: Stoykova
authors: Ales
authors: A
authors: Cvekl
authors: Jovica
authors: J
authors: Ninkovic
authors: Magdalena
authors: M
authors: Götz
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D055495:Neurogenesis / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins
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