Arx is required for specification of the zona incerta and reticular nucleus of the thalamus.
Mutations in the aristaless-related homeobox (ARX) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicating hypothalamic dysfunction, but little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects, we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in 2 different Arx mutant mouse lines at E18.5. Male mice engineered to have a polyalanine expansion mutation (Arx) revealed no expression differences in any diencephalic nucleus when compared with wild-type littermates. In contrast, mice null for Arx (Arx) lost expression of specific markers of the thalamic reticular nucleus and zona incerta (ZI) while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the dopaminergic A13 subnucleus of ZI, was among those lost, suggesting a requirement for Arx in normal thalamic reticular nucleus and ZI development and, specifically, for A13 dopaminergic fate. Because the ZI and A13 regions make connections to several hypothalamic nuclei, such misspecification may contribute to the "hypothalamic dysfunction" observed in some patients.
From the Department of Pathology, Children's Hospital of Philadelphia (CNS); Penn-PORT Program (CNS), and Department of Cell and Developmental Biology (JCS), University of Pennsylvania; and Department of Neurology, Children's Hospital of Philadelphia (EDM), Philadelphia, Pennsylvania; and Department of Pathology, Brigham Women and Children's Hospital, Boston, Massachusetts (JAG).
C Nicole
CN
Sunnen
Jacqueline C
JC
Simonet
Eric D
ED
Marsh
Jeffrey A
JA
Golden
D000818:Animals; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics*; D020530:Subthalamus / Q000378:metabolism*; D013787:Thalamic Nuclei / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
C469265:ARX protein, mouse; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D010455:Peptides; C497420:Six2 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; C019529:polyalanine; D014446:Tyrosine 3-Monooxygenase