Homolog of the Human Carpenter Syndrome Linked Gene, , Is Required for Synapse Development and Function.

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.