Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes.

Autor:	Karas BF; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Terez KR; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Mowla S; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Battula N; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Flannery KP; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Gural BM; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Aboussleman G; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Mubin N; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States., Manzini MC; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers University-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, United States.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Apr 08; Vol. 33 (8), pp. 709-723.
DOI:	10.1093/hmg/ddae006
Abstrakt:	Biallelic mutations in Protein 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. Removing Pomt1 in the mouse leads to early embryonic death due to the essential role of dystroglycan during placental formation in rodents. Here, we characterized and validated a model of pomt1 loss of function in the zebrafish showing that developmental defects found in individuals affected by dystroglycanopathies can be recapitulated in the fish. We also discovered that pomt1 mRNA 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, maternal pomt1 from heterozygous mothers was sufficient to sustain muscle, eye, and brain development only leading to 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. (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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