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Walcher, T. ; Xie, Q.* ; Sun, J.* ; Irmler, M. ; Beckers, J. ; Öztürk, T. ; Niessing, D. ; Stoykova, A.* ; Cvekl, A.* ; Ninkovic, J. ; Götz, M.-L.

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

Development 140, 1123-1136 (2013)
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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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter transcriptional regulator; radial glia; cortex development; mouse; Transcription Factor Pax6 ; Retinal Progenitor Cells ; Dna-binding Subdomains ; Small-eye ; Mutant Mice ; Mammalian Telencephalon ; Forebrain Development ; Sequence Recognition ; Developing Cortex ; Proneural Genes
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0950-1991
e-ISSN 1477-9129
Zeitschrift Development / Company of Biologists
Quellenangaben Band: 140, Heft: 5, Seiten: 1123-1136 Artikelnummer: , Supplement: ,
Verlag Company of Biologists
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)
Institute of Experimental Genetics (IEG)
Institute of Structural Biology (STB)
POF Topic(s) 30204 - Cell Programming and Repair
30201 - Metabolic Health
30203 - Molecular Targets and Therapies
Forschungsfeld(er) Stem Cell and Neuroscience
Genetics and Epidemiology
Enabling and Novel Technologies
PSP-Element(e) G-500800-001
G-500600-004
G-503091-001
PubMed ID 23404109
DOI 10.1242/dev.082875
WOS ID WOS:000314879800020
Scopus ID 84873723436
Erfassungsdatum 2013-02-12
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