ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c

Cereb Cortex. 2015 Feb;25(2):322-35. doi: 10.1093/cercor/bht222. Epub 2013 Aug 22.


Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx(-/Y) mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.

Keywords: TBR2; cell cycle; forebrain development; neurodevelopmental disorders; neurogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Cycle / physiology*
  • Cell Proliferation / physiology
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitosis / physiology
  • Neural Stem Cells / pathology
  • Neural Stem Cells / physiology*
  • Neurogenesis / physiology*
  • Neuroglia / pathology
  • Neuroglia / physiology
  • Neurons / pathology
  • Neurons / physiology
  • Olfactory Bulb / growth & development
  • Olfactory Bulb / pathology
  • Olfactory Bulb / physiopathology
  • Organ Size
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome


  • ARX protein, mouse
  • Cdkn1c protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p57
  • Homeodomain Proteins
  • Transcription Factors