Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG).

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene, located on Xp22.13. Arx-null mice show loss of tangential migration of GABAergic interneurons, presumably being related to caudal ganglionic eminence tangential migration. In the present study, we investigated a subpopulation of GABAergic interneurons in the brain of an infant with XLAG, who had a novel nonsense mutation of the ARX gene, compared with those of age-matched normal controls and Miller-Dieker syndrome. We performed immunocytochemistry for interneuron and migration markers. We found that glutamic acid decarboxylase (GAD)- and calretinin (CR)-containing cells were significantly reduced in the neocortex and located in the white matter and neocortical subventricular zone, while neuropeptide Y- or cholecystokinin-containing cells were normally distributed. Moreover, in the neocortical subventricular region, the GAD- and CR-containing cells expressed the radial migration marker Mash-1 as well as nestin. Our findings suggest that ARX protein controls not only the tangential migration of GABAergic interneurons from the ganglionic eminence, but also may serve to induce radial migration from the neocortical subventricular zone.
AuthorsShin Okazaki, Maki Ohsawa, Ichiro Kuki, Hisashi Kawawaki, Takeshi Koriyama, Shingou Ri, Hiroyuki Ichiba, Eishu Hai, Takeshi Inoue, Hiroaki Nakamura, Yu-Ichi Goto, Kiyotaka Tomiwa, Tsunekazu Yamano, Kunio Kitamura, Masayuki Itoh
JournalActa neuropathologica (Acta Neuropathol) Vol. 116 Issue 4 Pg. 453-62 (Oct 2008) ISSN: 1432-0533 [Electronic] Germany
PMID18458920 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ARX protein, human
  • CALB2 protein, human
  • Calb2 protein, mouse
  • Calbindin 2
  • Homeodomain Proteins
  • Neuropeptide Y
  • S100 Calcium Binding Protein G
  • Transcription Factors
  • gamma-Aminobutyric Acid
  • Cholecystokinin
  • Glutamate Decarboxylase
  • Adult
  • Amino Acid Sequence
  • Calbindin 2
  • Cell Movement
  • Cholecystokinin (metabolism)
  • Classical Lissencephalies and Subcortical Band Heterotopias (diagnosis, genetics, pathology)
  • Female
  • Genitalia, Male (abnormalities)
  • Glutamate Decarboxylase (metabolism)
  • Homeodomain Proteins (genetics, metabolism)
  • Humans
  • Infant
  • Interneurons (metabolism, pathology)
  • Male
  • Molecular Sequence Data
  • Mutation (genetics)
  • Neocortex (metabolism, pathology)
  • Neuropeptide Y (metabolism)
  • Pedigree
  • S100 Calcium Binding Protein G (metabolism)
  • Transcription Factors (genetics, metabolism)
  • gamma-Aminobutyric Acid (metabolism)

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