SEVERE MICROCEPHALY INDUCED BY BLOCKADE OF VASOACTIVE-INTESTINAL-PEPTIDE FUNCTION IN THE PRIMITIVE NEUROEPITHELIUM OF THE MOUSE
SEVERE MICROCEPHALY INDUCED BY BLOCKADE OF VASOACTIVE-INTESTINAL-PEPTIDE FUNCTION IN THE PRIMITIVE NEUROEPITHELIUM OF THE MOUSE
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DOI：
10.1172/jci117555
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发表时间：
1994-11-01
影响因子：
15.9
通讯作者：
BRENNEMAN, DE
中科院分区：
文献类型：
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作者：
GRESSENS, P;HILL, JM;BRENNEMAN, DE
血管活性肠肽(VIP)在细胞培养中具有强大的生长相关作用，影响细胞有丝分裂、神经元存活和神经分化。VIP还可以在体外移植后的小鼠胚胎中产生戏剧性的生长，其特征是细胞数量大幅增加。本研究的目的是评估VIP在体内早期神经系统发育中的作用。用血管活性肠肽的特异性拮抗剂处理妊娠小鼠。在发育早期(E9-E11)产前给予该拮抗剂会导致严重的小头畸形，其特征是胚胎脑重降低，DNA和蛋白质含量减少。与身体相比，生长迟缓在大脑中不成比例地表现出来，并通过与VIP共同治疗来防止。在妊娠后期使用相同的拮抗剂处理对胚胎生长没有明显影响。在胚胎发育的这一阶段，神经上皮细胞中仅限于中枢神经系统的血管活性肠肽受体在拮抗剂处理的胚胎中增加，而S期的细胞数量显著减少。因此，VIP在体内调节脑生长，抑制其作用为小头畸形的分子机制提供了新的见解。
Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell number. The goal of the present study was to assess the role of VIP on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-E11) produced severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionally manifested in the brain compared with the body and was prevented by co-treatment with VIP. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors, which were restricted to the central nervous system during this stage of embryonic development, were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides new insight into a molecular mechanism for microcephaly.