Lhx6 Directly Regulates Arx and CXCR7 to Determine Cortical Interneuron Fate and Laminar Position

Neuron. 2014 Apr 16;82(2):350-64. doi: 10.1016/j.neuron.2014.02.030.

Abstract

Cortical GABAergic interneurons have essential roles for information processing and their dysfunction is implicated in neuropsychiatric disorders. Transcriptional codes are elucidating mechanisms of interneuron specification in the MGE (a subcortical progenitor zone), which regulate their migration, integration, and function within cortical circuitry. Lhx6, a LIM-homeodomain transcription factor, is essential for specification of MGE-derived somatostatin and parvalbumin interneurons. Here, we demonstrate that some Lhx6⁻/⁻ MGE cells acquire a CGE-like fate. Using an in vivo MGE complementation/transplantation assay, we show that Lhx6-regulated genes Arx and CXCR7 rescue divergent aspects of Lhx6⁻/⁻ cell-fate and laminar mutant phenotypes and provide insight into a neonatal role for CXCR7 in MGE-derived interneuron lamination. Finally, Lhx6 directly binds in vivo to an Arx enhancer and to an intronic CXCR7 enhancer that remains active in mature interneurons. These data define the molecular identity of Lhx6 mutants and introduce technologies to test mechanisms in GABAergic interneuron differentiation.

Publication types

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

MeSH terms

  • Action Potentials / genetics
  • Age Factors
  • Animals
  • Cell Movement / genetics*
  • Cerebral Cortex / cytology*
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental / genetics
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • In Vitro Techniques
  • Interneurons / metabolism
  • Interneurons / physiology*
  • LIM-Homeodomain Proteins / genetics
  • LIM-Homeodomain Proteins / metabolism*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism*
  • Stem Cell Transplantation
  • Stem Cells / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • ARX protein, mouse
  • Chemokine CXCL1
  • Cmkor1 protein, mouse
  • Cxcl1 protein, mouse
  • Homeodomain Proteins
  • LHX6 protein, mouse
  • LIM-Homeodomain Proteins
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Receptors, CXCR
  • Transcription Factors
  • fluorescent protein 583