Poly (ADP-Ribose) Polymerase 1 Regulates Cajal-Retzius Cell Development and Neural Precursor Cell Adhesion

Poly (ADP-Ribose) Polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln. This correlates with an increased number of Cajal-Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion. mRNA profiles of wild-type (WT) and PARP1 KO E15.5 cortex (n = 4 of each genotype)聚(ADP-核糖)聚合酶1（Poly (ADP-Ribose) Polymerase 1, PARP1）是一种广泛表达的酶，可调控DNA损伤修复、细胞死亡、炎症反应与基因转录。PARP1的功能是以NAD+为供体，将ADP-核糖聚合物（ADP-ribose polymers, PAR）添加至包括自身在内的蛋白质上。这种被称为聚ADP核糖基化修饰（PARylation）的翻译后修饰，可改变PARP1及其底物蛋白的活性，且与多种神经系统疾病的发病机制密切相关。PARP1敲除小鼠表现出类精神分裂症行为，记忆形成受损，同时存在神经元增殖与存活缺陷；而影响聚ADP核糖基化修饰的基因突变，与人类的智力障碍、精神病、神经退行性疾病及中风相关。然而，目前PARP1在大脑发育中的作用尚未得到充分研究。本研究发现，PARP1缺失会导致大脑发育缺陷，并使新生个体的神经元密度升高。本研究进一步证实，PARP1缺失可上调胚胎发育第15.5天（E15.5）小鼠大脑皮层中与神经元迁移、黏附相关的基因（包括Reln）的表达水平。这与体内以及源自PARP1敲除小鼠皮层的胚胎神经祖细胞（embryonic neural progenitor cells, NPCs）培养物中卡哈尔-雷齐乌斯细胞（Cajal-Retzius cells, CR细胞）数量增加的现象相符。此外，PARP1缺失会增强胚胎神经祖细胞对N-钙黏蛋白（N-cadherin）的黏附能力，这与实验性暴露于Reelin蛋白所诱导的效应一致。综上，本研究结果揭示了PARP1在大脑发育中的全新功能，即调控CR细胞、神经元密度与细胞黏附。野生型（wild-type, WT）与PARP1敲除E15.5小鼠皮层的mRNA表达谱（每组基因型n=4）