Protein O-Mannosyltransferases in Development and Disease: Evolutionary and Functional Insights from Model Organisms.

Protein O-mannosylation is an evolutionarily conserved post-translational modification essential for neuromuscular development and physiology. The obligate heteromeric complex of protein O-mannosyltransferase 1 and 2 (POMT1/2) initiates O-mannosylation of α-dystroglycan and a limited number of known additional substrates in the endoplasmic reticulum. In humans, defects in these enzymes disrupt dystroglycan function, leading to impaired extracellular matrix interactions and causing a spectrum of severe congenital muscular dystrophies termed dystroglycanopathies. However, mounting evidence indicates that POMTs have additional functional substrates that substantially contribute to POMT1/2 mutant phenotypes through dystroglycan-independent mechanisms. This review examines POMT1/2 function through a comparative evolutionary lens of model organisms, such as Drosophila and zebrafish, and discusses O-mannosylation substrates beyond dystroglycan. We review the functions of POMT1/2 in muscles and the nervous system in Drosophila, including the interplay with receptor protein tyrosine phosphatases, a novel conserved family of substrates with essential functions in neural circuit formation. In the zebrafish model, POMT1/2 mutant phenotypes recapitulate multi-tissue defects associated with dystroglycanopathies, revealing compensatory mechanisms with broad implications for understanding these diseases and also suggesting the involvement of dystroglycan-independent pathomechanisms. Together, these animal models provide a tiered experimental framework, combining the advantages of simplified glycan architectures, powerful genetic tools, and comprehensively characterized development, with evolutionary conservation of core molecular players involved in human disease. These and other animal models will continue to make invaluable contributions towards dissecting POMT1/2 function at molecular, cellular, and genetic levels, leading to a better understanding of the pathological mechanisms of dystroglycanopathies.