Molecular pathology of neuronal differentiation, migration and death in developmental disorders.

a .神经元死亡我们制备了一种抗促进神经元凋亡蛋白Bak的多克隆抗体，并通过Western blotting和免疫染色研究了其在人脑中的表达。1996年，我们研究了与发育和衰老相关的变化，并证明了Bak在胎儿和老年大脑中的高表达。1997年，我们比较了唐氏综合征患者和对照组患者的Bak免疫反应性。在唐氏综合症的大脑中，与衰老相关的Bak上调过早发生。b .神经元分化我们制备了兔抗结节蛋白n和c末端的抗体，结节蛋白是TSC2基因的产物，负责结节性硬化症。1996年，我们在对照脑中证实了tuberin的表达。在发育过程中，tuberin含量随年龄增长而增加。相比之下，结节性硬化症的大脑显示结节蛋白的缺失，在错构瘤病变（皮质结节和室管膜下巨细胞瘤）和组织学上正常的皮层中，结节蛋白的缺失都很严重。肾和心脏错构瘤也失去了结节素免疫反应性。1997年，我们在局灶性皮质发育不良中观察到正常水平的结节蛋白表达，从而表明结节性硬化症和皮质发育不良之间的病理生理差异。c .神经元迁移我们扩展了LIS1基因产物（PAF乙酰水解酶的45k亚基）的免疫组织化学研究，该基因缺陷是导致米勒-迪克尔无脑畸形综合征的原因。1996年，我们研究了LIS1在各种迁移障碍中的表达，并证明LIS1的缺失是该综合征特有的。1997年，我们对人类胎儿大脑进行免疫染色，观察到脑室神经上皮和Cajal-Retzius细胞的强标记。

A.Neuronal deathWe produced a polyclonal antibody against Bak, a protein promoting neuronal apoptosis, and thereby studied its expression in human brains by Western blotting and immunostaining. In 1996, we investigated the changes associated with development and aging, and demonstrated that the expression of Bak is high in the fetal and aged brains. In 1997, we comapared Bak immunoreactivity between Down syndrome and control patients. In Down syndrome brains, the aging-related upregulation of Bak occurred prematurely. Cerebral neurons became Bak-positive prior to the development of neurofibrillary changes.B.Neuronal differentiationWe produced rabbit antibodies against the N-and C-terminal of tuberin, the product of the TSC2 gene responsible for tuberous sclerosis. In 1996, we demonstrated the expression of tuberin in control cerebra. During development, tuberin content increased with age. Tuberous sclerosis brains by contrast showed loss of tuberin, which was severe in both the hamartomatous lesions (cortical tuber and subependymal giant cell tumor) and histologically normal cortices. Tuberin immunoreactivity was also lost from the renal and cardiac hamartomas. In 1997, we observed a normal level of tuberin expression in focal cortical dysplasia, thereby indicating pathophysiological difference between tuberous sclerosis and cortical dysplasia.C.Neuronal migrationWe extended immunohistochemical studies of the LIS1 gene product (a 45k subunit of PAF acetylhydrolase), the defect of which being responsible for the Miller-Dieker lissencephaly syndrome. In 1996, we studied the expression of LIS1 in various migration disorders, and demonstrated that the loss of LIS1 is specific to the syndrome. In 1997, we immunostained human fetal brains and observed strong labeling of the ventricular neuroepithlium and Cajal-Retzius cells.