Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas 78229.
Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
J Neurosci. 2022 Sep 14;42(37):7016-7030. doi: 10.1523/JNEUROSCI.0442-22.2022. Epub 2022 Aug 9.
multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human encodes a multidomain transmembrane protein which is highly conserved across species. In humans, mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects, and learning disabilities. is also associated with psychiatric disorders. Despite its clinical relevance, remains poorly characterized; and although it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of with psychiatric disorders indicate that mutations in cause underlying defects in synaptic structure and functions. In this study, we investigated the role of dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synapses and is required for proper synaptic growth. mutant larvae and adults show severe motor coordination deficits. At the NMJ, mutants show altered localization of presynaptic and postsynaptic proteins, defects in synaptic ultrastructure, and neurotransmission. Interestingly, mutants have reduced levels of the Type II BMP receptor Wishful thinking (). displays genetic interactions with () and , and in association with Dnrx and Wit plays an essential role in synapse organization. Our studies provide insights into human MEGF8 functions and potentially into mechanisms that may underlie intellectual disabilities observed in Carpenter syndrome as well as MEGF8-related synaptic structural and/or functional deficits in psychiatric disorders. Carpenter syndrome, known for over a century now, is a genetic disorder linked to mutations in () gene and associated with intellectual disabilities among other symptoms. is also associated with psychiatric disorders. Despite the high genetic conservation and clinical relevance, the functions of remain largely uncharacterized. Patients with intellectual disabilities and psychiatric diseases often have an underlying defect in synaptic structure and function. This work defines the role of the fly homolog of human , , in glutamatergic synapse growth, organization, and function and provide insights into potential functions of in human central synapses and synaptic mechanisms that may underlie psychiatric disorders and intellectual disabilities seen in Carpenter syndrome.
多个表皮生长因子样结构域 8 (dMegf8) 是人类同源物，它编码一种具有多个结构域的跨膜蛋白，在物种间高度保守。在人类中，突变导致一种罕见的遗传疾病，称为 Carpenter 综合征，常伴有左右模式异常、心脏缺陷和学习障碍。还与精神疾病有关。尽管它具有临床相关性，但仍未得到充分表征；尽管它高度保守，但对 Megf8 动物模型的研究也非常有限。Carpenter 综合征患者存在智力障碍，与精神疾病有关，表明突变导致突触结构和功能的潜在缺陷。在这项研究中，我们研究了 dMegf8 在雄性和雌性幼虫神经肌肉接头 (NMJ) 的谷氨酸能突触中的作用。我们表明，dMegf8 定位于 NMJ 突触，是突触正常生长所必需的。突变体幼虫和成虫表现出严重的运动协调缺陷。在 NMJ 处，突变体表现出突触前和突触后蛋白定位改变、突触超微结构缺陷和神经递质传递异常。有趣的是，突变体的 WISH 蛋白（一种 II 型 BMP 受体）水平降低。与（）和（）显示遗传相互作用，与 Dnrx 和 Wit 一起在突触组织中发挥重要作用。我们的研究提供了对人类 MEGF8 功能的深入了解，并可能提供了导致 Carpenter 综合征中观察到的智力障碍以及精神疾病中 MEGF8 相关突触结构和/或功能缺陷的潜在机制的见解。Carpenter 综合征，一个多世纪以来众所周知，是一种与基因突变相关的遗传疾病（）基因，与智力障碍等其他症状有关。还与精神疾病有关。尽管遗传高度保守且具有临床相关性，但的功能仍在很大程度上未被描述。智力障碍和精神疾病患者的突触结构和功能通常存在潜在缺陷。这项工作定义了人类同源物果蝇的作用，在谷氨酸能突触生长、组织和功能中，并提供了对人类中枢突触和突触机制的潜在功能的深入了解，这些机制可能是 Carpenter 综合征和智力障碍相关的精神疾病的基础。
