Recent studies have reported that complement-related proteins modulate brain development through regulating synapse processes in the cortex. CSMD3 belongs to a group of putative complement control proteins. However, its role in the central nervous system and synaptogenesis remains largely unknown. Here we report that CSMD3 deleterious mutations occur frequently in patients with neurodevelopmental disorders (NDDs). Csmd3 is predominantly expressed in cortical neurons of the developing cortex. In mice, Csmd3 disruption induced retarded development and NDD-related behaviors. Csmd3 deficiency impaired synaptogenesis and neurogenesis, allowing fewer neurons reaching the cortical plate. Csmd3 deficiency also induced perturbed functional networks in the developing cortex, involving a number of downregulated synapse-associated genes that influence early synaptic organization and upregulated genes related to immune activity. Our study provides mechanistic insights into the endogenous regulation of complement-related proteins in synaptic development and supports the pathological role of CSMD3 in NDDs.

最近的研究报告称，补体相关蛋白通过调节皮质中的突触过程来调节大脑发育。CSMD3 属于一组推定的补体控制蛋白。然而，它在中枢神经系统和突触发生中的作用仍然很大程度上未知。在这里，我们报告CSMD3有害突变经常发生在患有神经发育障碍 (NDD) 的患者中。Csmd3主要在发育皮层的皮层神经元中表达。在小鼠中，Csmd3破坏会导致发育迟缓和 NDD 相关行为。Csmd3缺乏会损害突触发生和神经发生，使到达皮质板的神经元减少。Csmd3缺乏还会导致发育中的皮层功能网络受到干扰，涉及许多影响早期突触组织的下调突触相关基因和与免疫活动相关的上调基因。我们的研究为补体相关蛋白在突触发育中的内源性调控提供了机制见解，并支持CSMD3在 NDDs 中的病理作用。