Transcriptomics

Dataset Information

5

Functional dissection of the Paired domain of Pax6 – distinct roles of subdomains in neurogenesis and proliferation


ABSTRACT: The transcription factor Pax6 acts as a key developmental regulator in various organs. In the developing brain Pax6 regulates patterning, neurogenesis and proliferation, but how these diverse effects are mediated at the molecular level is not well understood. As Pax6 regulates forebrain development including neurogenesis, proliferation and patterning, almost exclusively by one of its DNA-binding domains, the bipartite paired domain, we examined the role of its respective DNA-binding subdomains (PAI and RED). Using mice with point mutations in the PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C) subdomains we unravelled opposing roles of mutations in these subdomains in regulating genes that control proliferation in the developing cerebral cortex. Mutation of the PAI domain reduced proliferation of both apical and basal progenitors, while the RED domain mutation significantly increased proliferation. Conversely, neurogenesis was affected only by the PAI domain mutation phenocopying the neurogenic defects observed in full Pax6 mutants. Genome-wide expression analysis supported the molecularly distinct signature upon mutation of these subdomains unravelling the key neurogenic signature mediated by the PAI domain. The altered expression of genes identified as direct Pax6 targets by chromatin immunoprecipitation allowed to further identify regulatory elements whose function was impaired by each individual Pax6 mutated protein. Thus, Pax6 achieves its key roles in the developing forebrain by utilizing distinct subdomains to regulate neurogenesis and exert opposing effects on proliferation, while Pax6-target genes involved in patterning tolerate either subdomain mutation. We performed gene expression microarray analysis of Pax6 mutant mice (Leca2, Leca4, Sey) and control mice

ORGANISM(S): Mus musculus  

SUBMITTER: Jovica Ninkovic   Magdalena Goetz  Tessa Walcher  Ales Cvekl  Dierk Nissing  Magdalena Götz  Martin Irmler  Qing Xie  Johannes Beckers  Anastassia Stoykova 

PROVIDER: E-GEOD-35260 | ArrayExpress | 2013-03-19

SECONDARY ACCESSION(S): GSE35260PRJNA152833

REPOSITORIES: GEO, ArrayExpress

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Publications

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

Walcher Tessa T   Xie Qing Q   Sun Jian J   Irmler Martin M   Beckers Johannes J   Öztürk Timucin T   Niessing Dierk D   Stoykova Anastassia A   Cvekl Ales A   Ninkovic Jovica J   Götz Magdalena M  

Development (Cambridge, England) 20130301 5


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  ...[more]

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