Removal ofpomt1in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes

Abstract

AbstractBiallelic mutations inProtein O-mannosyltransferase 1(POMT1) are among the most common causes of a severe group of congenital muscular dystrophies (CMDs) known as dystroglycanopathies. POMT1 is a glycosyltransferase responsible for the attachment of a functional glycan mediating interactions between the transmembrane glycoprotein dystroglycan and its binding partners in the extracellular matrix (ECM). Disruptions in these cell-ECM interactions lead to multiple developmental defects causing brain and eye malformations in addition to CMD. RemovingPomt1in the mouse leads to early embryonic death due to the essential role of dystroglycan in embryo implantation in rodents. Here, we characterized and validated a model ofpomt1loss of function in the zebrafish showing that developmental defects found in individuals affected by dystroglycanopathies can be recapitulated in the fish. We also discovered thatpomt1mRNA provided by the mother in the oocyte supports dystroglycan glycosylation during the first few weeks of development. Muscle disease, retinal synapse formation deficits, and axon guidance defects can only be uncovered during the first week post fertilization by generating knock-out embryos from knock-out mothers. Conversely, maternalpomt1from heterozygous mothers was sufficient to sustain muscle, eye, and brain development only leading to detectable muscle disease and loss of photoreceptor synapses at 30 days post fertilization. Our findings show that it is important to define the contribution of maternal mRNA while developing zebrafish models of dystroglycanopathies and that offspring generated from heterozygous and knock-out mothers can be used to differentiate the role of dystroglycan glycosylation in tissue formation and maintenance.