Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons

Dev Dyn. 2004 Nov;231(3):631-9. doi: 10.1002/dvdy.20164.


Mutations in the human ARX gene show unusually heterogeneous clinical presentations, including syndromic and nonsyndromic mental retardation, myoclonic epilepsy with spasticity, and lissencephaly with abnormal genitalia, that are believed to arise from an impairment of the embryonic mechanisms building the anterior central nervous system structures. Here, we show that the murine ortholog Arx has a highly dynamic expression pattern during both early shaping of the forebrain vesicle and later major events of neural migrations and cell-type specification. Early on, the Arx gene is specifically activated in anterior forebrain anlage. Afterward, Arx expression is confined to the telencephalic vesicles and is enhanced during differentiation of the subpallial structures of the ganglionic eminences, overlapping with Dlx2, Dlx5, and Gad1 transcriptional domains. Tangentially migrating neurons reaching the cortical plate are also Arx-positive at all embryonic stages analyzed. RNA-protein colabeling staining shows that Arx expression is maintained in the mature cortical interneurons, suggesting its involvement in the different functions of the gamma-aminobutyric acid (GABA)ergic neurons settled into the adult cerebral cortex. Finally, Arx expression is detected in the anterior subventricular layer of the adult brain, where neural stem cells have been shown to be located. Of interest, Arx expression is highly up-regulated during in vitro differentiation of pure neural stem cell cultures retrieved from adult brain. All together, these findings suggest Arx as a gene involved in the commitment of proliferating neuroblasts into a GABAergic neuronal fate. In conclusion, our mouse Arx expression data provide important further insights into the puzzling complexity of the human ARX mutation pleiotropy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers
  • Cell Differentiation
  • Cells, Cultured
  • Culture Media
  • Embryonic Development
  • Epilepsy / genetics*
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Humans
  • In Situ Hybridization
  • Mental Retardation, X-Linked / genetics*
  • Mice
  • Mutation
  • Neurons / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / embryology
  • Prosencephalon / metabolism*
  • Stem Cells*
  • Transcription Factors / genetics*
  • gamma-Aminobutyric Acid / metabolism*


  • ARX protein, mouse
  • Biomarkers
  • Culture Media
  • Homeodomain Proteins
  • Transcription Factors
  • gamma-Aminobutyric Acid