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.
Highlights
The paired box protein, Pax6, is a highly conserved transcription factor of 422 amino acids comprising two DNA-binding domains, an amino-terminal paired domain and a homeodomain along with a carboxyterminal proline/serine/threonine-rich transactivation domain [1, 2]
Pax6 is highly expressed in ventricular zone (VZ) and is gradually lost as cells progress through the subventricular zone (SVZ) to the cortical plate (CP; Supplementary Figure S1A)
We attempted to uncover genes under the transcriptional control of Pax6 in NPs and identified downstream transcription factors that contribute to neurogenesis
Summary
The paired box protein, Pax, is a highly conserved transcription factor of 422 amino acids comprising two DNA-binding domains, an amino-terminal paired domain and a homeodomain along with a carboxyterminal proline/serine/threonine-rich transactivation domain [1, 2]. The discovery of a plethora of known Pax functions has been facilitated by various Pax mutants One such very useful mutant, the small eye (Sey) mouse mutant, contains a single-base substitution [11], resulting in the production of a functionally inactive and truncated Pax lacking the DNA-binding homeodomain and the C-terminal activation domain. The Sey mutant mouse phenotype is similar to that of an artificially targeted Pax6-deficient mouse (Pax6−ax), showing small eyes and numerous neural defects, including reduced neurons in the cerebral cortex [11,12,13]. These phenotypic similarities in the Sey mutant and Pax6− ax substantiate the use of Sey homozygous mutant mice as Pax6-null mutants. It was further shown that Sey mutant embryonic stem (ES) cells generate misspecified neurons that undergo death because of high expression of the neurotrophin receptor p75NTR [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
