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.
Okazaki
Shin
S
Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.
Ohsawa
Maki
M
Kuki
Ichiro
I
Kawawaki
Hisashi
H
Koriyama
Takeshi
T
Ri
Shingou
S
Ichiba
Hiroyuki
H
Hai
Eishu
E
Inoue
Takeshi
T
Nakamura
Hiroaki
H
Goto
Yu-Ichi
Y
Tomiwa
Kiyotaka
K
Yamano
Tsunekazu
T
Kitamura
Kunio
K
Itoh
Masayuki
M
D000328:Adult; D000595:Amino Acid Sequence; D064032:Calbindin 2; D002465:Cell Movement; D002766:Cholecystokinin / Q000378:metabolism; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D000089662:Doublecortin Protein; D005260:Female; D005837:Genitalia, Male / Q000002:abnormalities*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007395:Interneurons / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019579:Neocortex / Q000378:metabolism / Q000473:pathology*; D009478:Neuropeptide Y / Q000378:metabolism; D010375:Pedigree; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C469264:ARX protein, human; C576764:CALB2 protein, human; C576511:Calb2 protein, mouse; D064032:Calbindin 2; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D009478:Neuropeptide Y; D064030:S100 Calcium Binding Protein G; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; D005968:Glutamate Decarboxylase