Zellweger syndrome (ZS), a neonatal lethal disorder arising from defective peroxisome biogenesis, features profound neuroanatomical abnormalities and brain dysfunction. Here we used mice with brain-restricted inactivation of the peroxisome biogenesis gene PEX13 to model the pathophysiological features of ZS, and determine the impact of peroxisome dysfunction on neurogenesis and cell maturation in ZS. In the embryonic and postnatal PEX13 mutant brain, we demonstrate key regions with altered brain anatomy, including enlarged lateral ventricles and aberrant cortical, hippocampal and hypothalamic organization. To characterize the underlying mechanisms, we show a significant reduction in proliferation, migration, differentiation, and maturation of neural progenitors in embryonic E12.5 through to P3 animals. An increasing reactive gliosis in the PEX13 mutant brain started at E14.5 in association with the pathology. Together with impaired neurogenesis and associated gliosis, our data demonstrate increased cell death contributing to the hallmark brain anatomy of ZS. We provide unique data where impaired neurogenesis and migration are shown as critical events underlying the neuropathology and altered brain function of mice with peroxisome deficiency.

Zellweger综合征（ZS）是一种由过氧化物酶体生物发生缺陷引起的新生儿致死性疾病，具有深刻的神经解剖学异常和脑功能障碍。在这里，我们使用过氧化物酶体生物发生基因PEX13的大脑限制性失活小鼠来模拟ZS的病理生理特征，并确定过氧化物酶体功能障碍对ZS中神经发生和细胞成熟的影响。在胚胎和出生后的PEX13突变型大脑中，我们证实了大脑解剖结构发生变化的关键区域，包括侧脑室增大以及皮层，海马和下丘脑组织异常。为了表征潜在的机制，我们显示了胚胎E12.5到P3动物中神经祖细胞的增殖，迁移，分化和成熟显着减少。PEX13突变型脑中增加的反应性神经胶质增生始于与病理相关的E14.5。与受损的神经发生和相关的神经胶质细胞增生一起，我们的数据表明细胞死亡增加，助长了ZS的标志性大脑解剖结构。我们提供了独特的数据，其中将神经发生和迁移受损显示为过氧化物酶体缺乏症小鼠神经病理学和脑功能改变的关键事件。