Cystathionine β-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS
Cystathionine β-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS
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DOI：
10.1096/fj.05-3724fje
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发表时间：
2005-09-01
期刊：
影响因子：
4.8
通讯作者：
Kimura, H
中科院分区：
文献类型：
--
作者：
Enokido, Y;Suzuki, E;Kimura, H
半胱硫氨酸β -合成酶（CBS; EC 4.2.1.22）是蛋氨酸生成半胱氨酸的关键酶。缺乏CBS导致同型半胱氨酸尿，这是一种以智力迟钝、癫痫、精神障碍、骨骼异常和血管疾病为特征的遗传性人类疾病；然而，潜在的机制在很大程度上仍然未知。在这里，我们展示了CBS在成年和发育中的小鼠大脑中的区域和细胞分布。在成年小鼠大脑中，CBS普遍表达，但在小脑分子层和海马齿状回表达最强烈。免疫组织化学分析显示，CBS在小脑伯格曼胶质细胞和整个大脑的星形胶质细胞中优先表达。在发育早期，CBS在脑室区的神经上皮细胞中表达，但在胚胎晚期和新生儿期，其表达转变为放射状胶质细胞，然后转变为星形胶质细胞。CBS在青少年大脑中表达最高，并且在培养的星形胶质细胞中观察到对EGF、tgf - α、cAMP和地塞米松的显著诱导。此外，kainic酸诱导癫痫发作后，CBS在海马反应性星形胶质细胞中显著积累，CBS缺陷小鼠的小脑形态出现异常。综上所述，这些结果表明，CBS在中枢神经系统的发育和维持中起着至关重要的作用，而放射状胶质细胞/星形胶质细胞功能障碍可能参与了与异常同型半胱氨酸代谢相关的复杂神经病理特征。
Cystathionine beta-synthase (CBS; EC 4.2.1.22) is a key enzyme in the generation of cysteine from methionine. A deficiency of CBS leads to homocystinuria, an inherited human disease characterized by mental retardation, seizures, psychiatric disturbances, skeletal abnormalities, and vascular disorders; however, the underlying mechanisms remain largely unknown. Here, we show the regional and cellular distribution of CBS in the adult and developing mouse brain. In the adult mouse brain, CBS was expressed ubiquitously, but it is expressed most intensely in the cerebellar molecular layer and hippocampal dentate gyrus. Immunohistochemical analysis revealed that CBS is preferentially expressed in cerebellar Bergmann glia and in astrocytes throughout the brain. At early developmental stages, CBS was expressed in neuroepithelial cells in the ventricular zone, but its expression changed to radial glial cells and then to astrocytes during the late embryonic and neonatal periods. CBS was most highly expressed in juvenile brain, and a striking induction was observed in cultured astrocytes in response to EGF, TGF-alpha, cAMP, and dexamethasone. Moreover, CBS was significantly accumulated in reactive astrocytes in the hippocampus after kainic acid-induced seizures, and cerebellar morphological abnormalities were observed in CBS-deficient mice. Taken together, these results suggest that CBS plays a crucial role in the development and maintenance of the CNS and that radial glia/astrocyte dysfunction might be involved in the complex neuropathological features associated with abnormal homocysteine metabolism.