Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb

Da Mi; Catherine B Carr; Petrina A Georgala; Yu-Ting Huang; Martine N Manuel; Emily Jeanes; Emi Niisato; Stephen N Sansom; Frederick J Livesey; Thomas Theil; Kerstin Hasenpusch-Theil; T Ian Simpson; John O Mason; David J Price

doi:10.1016/j.neuron.2013.02.012

Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb

Neuron. 2013 Apr 24;78(2):269-84. doi: 10.1016/j.neuron.2013.02.012.

Authors

Da Mi¹, Catherine B Carr, Petrina A Georgala, Yu-Ting Huang, Martine N Manuel, Emily Jeanes, Emi Niisato, Stephen N Sansom, Frederick J Livesey, Thomas Theil, Kerstin Hasenpusch-Theil, T Ian Simpson, John O Mason, David J Price

Affiliation

¹ Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.

Abstract

The mechanisms by which early spatiotemporal expression patterns of transcription factors such as Pax6 regulate cortical progenitors in a region-specific manner are poorly understood. Pax6 is expressed in a gradient across the developing cortex and is essential for normal corticogenesis. We found that constitutive or conditional loss of Pax6 increases cortical progenitor proliferation by amounts that vary regionally with normal Pax6 levels. We compared the gene expression profiles of equivalent Pax6-expressing progenitors isolated from Pax6⁺/⁺ and Pax6⁻/⁻ cortices and identified many negatively regulated cell-cycle genes, including Cyclins and Cdks. Biochemical assays indicated that Pax6 directly represses Cdk6 expression. Cyclin/Cdk repression inhibits retinoblastoma protein (pRb) phosphorylation, thereby limiting the transcription of genes that directly promote the mechanics of the cell cycle, and we found that Pax6 inhibits pRb phosphorylation and represses genes involved in DNA replication. Our results indicate that Pax6's modulation of cortical progenitor cell cycles is regional and direct.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Patterning / genetics*
Bromodeoxyuridine
Cell Cycle / genetics
Cell Proliferation
Cerebral Cortex / cytology*
Chromatin Immunoprecipitation
Cyclin-Dependent Kinase 6 / genetics
Cyclin-Dependent Kinase 6 / metabolism*
Embryo, Mammalian
Eye Proteins / genetics
Eye Proteins / metabolism*
Gene Expression Regulation, Developmental
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Mice
Mice, Transgenic
PAX6 Transcription Factor
PAX7 Transcription Factor / genetics
Paired Box Transcription Factors / genetics
Paired Box Transcription Factors / metabolism*
Phosphorylation
Protein Binding / genetics
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism*
Stem Cells / physiology*
Transcription Factors / genetics

Substances

Eye Proteins
Homeodomain Proteins
Luminescent Proteins
PAX6 Transcription Factor
PAX7 Transcription Factor
Paired Box Transcription Factors
Pax6 protein, mouse
Pax7 protein, mouse
Repressor Proteins
Retinoblastoma Protein
Transcription Factors
empty spiracles homeobox proteins
Cdk6 protein, mouse
Cyclin-Dependent Kinase 6
Bromodeoxyuridine

Abstract

Publication types

MeSH terms

Substances

Grants and funding