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).
J Neuropathol Exp Neurol. 2014 Mar;73(3):253-61. doi: 10.1097/NEN.0000000000000048.
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.
ARX 基因突变导致一系列结构和功能神经系统疾病，包括无脑回畸形、运动障碍、智力障碍和癫痫。一些患者还存在下丘脑功能障碍的症状，但 ARX 在间脑发育中的作用知之甚少。为了开始评估间脑缺陷，我们在 E18.5 时检查了两个不同的 Arx 突变小鼠系中一组已知基因和基因产物的表达，这些基因和基因产物标记特定的间脑核。与野生型同窝仔相比，带有多聚丙氨酸扩展突变（Arx）的雄性小鼠在任何间脑核中均未显示出表达差异。相比之下，Arx 缺失（Arx）的小鼠失去了丘脑网状核和中间核（ZI）的特定标志物的表达，而在其他丘脑核和下丘脑保留了表达。酪氨酸羟化酶是 ZI 的 A13 亚核多巴胺能的标志物，它是丢失的标志物之一，这表明 Arx 对正常丘脑网状核和 ZI 发育，特别是对 A13 多巴胺能命运有要求。由于 ZI 和 A13 区域与几个下丘脑核相连，因此这种错位可能导致一些患者观察到的“下丘脑功能障碍”。
