A large number of cells undergo apoptosis via caspase activation during and after neural tube closure (NTC) in mammals. Apoptosis is executed by either intrinsic or extrinsic apoptotic pathways, and inhibition of each pathway causes developmental defects around NTC stages, which hampers the physiological roles of apoptosis and caspases after NTC. We generated transgenic mice in which a broad spectrum of caspases could be suppressed in a spatiotemporal manner by pan-caspase inhibitor protein p35 originating from baculovirus. Mice with nervous system-specific expression of p35 (Nestin-Cre (NCre);p35V mice) exhibited postnatal lethality within 1 month after birth. They were born at the expected Mendelian ratio, but demonstrated severe postnatal growth retardation and hydrocephalus. The flow of cerebrospinal fluid (CSF) between the third and fourth ventricles was disturbed, whereas neither stenosis nor abnormality in ciliary morphology was observed in the pathway of CSF flow. Hydrocephalus and growth retardation of NCre;p35V mice were not rescued by the deletion of RIPK3, an essential factor for necroptosis which occurs in the absence of caspase-8 activation during development. The CSF of NCre;p35V mice contained a larger amount of secreted proteins than that of the controls. These findings suggest that the establishment of proper CSF dynamics requires caspase activity during brain development after NTC.

在哺乳动物的神经管闭合 (NTC) 期间和之后，大量细胞通过半胱天冬酶激活经历凋亡。细胞凋亡是通过内在或外在凋亡途径执行的，每个途径的抑制都会导致 NTC 阶段周围的发育缺陷，这阻碍了 NTC 后细胞凋亡和半胱天冬酶的生理作用。我们生成了转基因小鼠，其中可以通过源自杆状病毒的泛半胱天冬酶抑制剂蛋白 p35 以时空方式抑制广谱半胱天冬酶。具有神经系统特异性 p35 表达的小鼠 ( Nestin-Cre (NCre);p35V小鼠）在出生后 1 个月内表现出产后致死率。他们以预期的孟德尔比率出生，但表现出严重的出生后生长迟缓和脑积水。脑脊液（CSF）在第三和第四脑室之间流动受到干扰，而在脑脊液流动通路中未观察到狭窄和纤毛形态异常。脑积水和NCre 的生长迟缓；p35V小鼠没有因RIPK3的缺失而获救，RIPK3 是在发育过程中缺乏 caspase-8 激活时发生的坏死性凋亡的重要因素。NCre的脑脊液；p35V小鼠含有比对照组更多的分泌蛋白。这些发现表明，在 NTC 后大脑发育过程中，适当的 CSF 动力学的建立需要半胱天冬酶活性。