The CB(1) cannabinoid receptor drives corticospinal motor neuron differentiation through the Ctip2/Satb2 transcriptional regulation axis

J Neurosci. 2012 Nov 21;32(47):16651-65. doi: 10.1523/JNEUROSCI.0681-12.2012.


The generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB(1) cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB(1) receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB(1)(-/-) mice and in glutamatergic neuron-specific Nex-CB(1)(-/-) mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult mice. Likewise, genetic deletion of CB(1) receptors in Thy1-YFP-H mice elicited alterations in corticospinal tract development. Altogether, these data demonstrate that the CB(1) receptor contributes to the generation of deep-layer cortical neurons by coupling endocannabinoid signals from the neurogenic niche to the intrinsic proneurogenic Ctip2/Satb2 axis, thus influencing appropriate subcerebral projection neuron specification and corticospinal motor function in the adulthood.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Cell Differentiation / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Immunohistochemistry
  • In Situ Hybridization
  • Matrix Attachment Region Binding Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Motor Neurons / physiology*
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology
  • Protein Kinase C / metabolism
  • Pyramidal Cells / physiology*
  • Pyramidal Tracts / cytology
  • Pyramidal Tracts / physiology*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Cannabinoid, CB1 / physiology*
  • Repressor Proteins / physiology*
  • Transcription Factors / physiology*
  • Tumor Suppressor Proteins / physiology*


  • Bcl11b protein, mouse
  • Matrix Attachment Region Binding Proteins
  • Receptor, Cannabinoid, CB1
  • Repressor Proteins
  • SATB2 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins
  • protein kinase C gamma
  • Protein Kinase C