Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex

Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21924-9. doi: 10.1073/pnas.0909894106. Epub 2009 Dec 3.

Abstract

The link between cortical precursors G1 duration (TG1) and their mode of division remains a major unresolved issue of potential importance for regulating corticogenesis. Here, we induced a 25% reduction in TG1 in mouse cortical precursors via forced expression of cyclin D1 and cyclin E1. We found that in utero electroporation-mediated gene transfer transfects a cohort of synchronously cycling precursors, necessitating alternative methods of measuring cell-cycle phases to those classical used. TG1 reduction promotes cell-cycle reentry at the expense of differentiation and increases the self-renewal capacities of Pax6 precursors as well as of Tbr2 basal precursors (BPs). A population level analysis reveals sequential and lineage-specific effects, showing that TG1 reduction: (i) promotes Pax6 self-renewing proliferative divisions before promoting divisions wherein Pax6 precursors generate Tbr2 BPs and (ii) promotes self-renewing proliferative divisions of Tbr2 precursors at the expense of neurogenesis, thus leading to an amplification of the BPs pool in the subventricular zone and the dispersed mitotic compartment of the intermediate zone. These results point to the G1 mode of division relationship as an essential control mechanism of corticogenesis. This is further supported by long-term studies showing that TG1 reduction results in cytoarchitectural modifications including supernumerary supragranular neuron production. Modeling confirms that the TG1-induced changes in neuron production and laminar fate are mediated via the changes in the mode of division. These findings also have implications for understanding the mechanisms that have contributed to brain enlargement and complexity during evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Division*
  • Cerebral Cortex / cytology*
  • Electroporation
  • Eye Proteins / genetics
  • Female
  • G1 Phase*
  • Homeodomain Proteins / genetics
  • Mice
  • Neurons / cytology*
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Phenotype
  • Pregnancy
  • RNA, Small Interfering
  • Repressor Proteins / genetics

Substances

  • Eye Proteins
  • Homeodomain Proteins
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • RNA, Small Interfering
  • Repressor Proteins