title: Mapping gene regulatory circuitry of Pax6 during neurogenesis.
abstract: Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that Pax6 targets a large number of promoters in neural progenitors cells. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6-binding data set with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes, thereby ensuring the unidirectionality of lineage commitment towards neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74, during brain development impairs polarity and migration of newborn neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program.
authors.affiliation: Institute of Molecular Biology (IMB), Ackermannweg 4 , Mainz, Germany.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Thakurela
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 19 , Mainz, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: Institute of Molecular Biology (IMB), Ackermannweg 4 , Mainz, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schick
authors.affiliation: Institute of Molecular Biology (IMB), Ackermannweg 4 , Mainz, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Garding
authors.affiliation: Department of Biomedicine, University of Basel , Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Ivanek
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 19, Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, Germany.
authors.forename: Benedikt
authors.identifier: 0000-0003-2652-2782
authors.initials: B
authors.lastname: Berninger
authors.affiliation: Institute of Molecular Biology (IMB), Ackermannweg 4 , Mainz, Germany.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Tiwari
keywords: Chromatin; Gene regulation; Neural progenitors; Neurogenesis; Transcription Factors