Characterization of the pathogenic Mab21l2 R51C allele in early eye development

Abstract

The M̲ale A̲b̲normal-21 (mab-21) was first discovered in Caenorhabditis elegans (C. elegans) as a cell fate determinant, working under the TGF-β/DBL-1 signalling pathway in controlling the development of male tail. The mab-21 is evolutionarily conserved in terms of protein sequence and expression pattern. The vertebrate homolog Mab21l1 and Mab21l2 are identified in various species including xenopus, zebrafish, chicken, mouse and human. Mab21l2 expression profiling and loss of function study in murine indicated the gene functions in the developing neural tissue and bone, and it is essential for embryo’s survival. Recently, missense mutations in human MAB21L2 were identified in patients with a spectrum of malformed eyes. The Mab21l2(R51C) mutation is one of the identified dominant mutations and caused the most severe phenotype. To evaluate the pathology of the Mab21l2 R51C allele, our lab had successfully knock-in the R51C mutation into the mouse genome. The pathogenesis of this dominant allele in early eye development is characterized in this study. The Mab21l2 R51C allele interferes multiple stages in early eye development. The less extended optic vesicle with extensive cell death in the distal region reveals its phenotypic onset at embryonic stage E10. The optic vesicle in Mab21l2^R51C/+ mutant loses the competency for lens induction, ectodermal lens induction marker Sox2 is not upregulated, and lens placode/lens vesicle are not formed. In the Mab21l2^R51C/+ mutant, the retinal pigmented epithelium is thickened, expressing Mab21l2 R51C/Mab21l2, having extensive proliferation (E10.5) and has not been specified into the pigmented monolayer as observed in wildtype (E11.5), indicating Mab21l2 R51C could prevent cell differentiation in the retinal progenitor cell. Further evidence has shown that this R51C dominant mutation is not a loss of function mutation. Mab21l2 R51C overexpression in P19 cells has a comparable function as the overexpressing of the wildtype Mab21l2, including the Pax6 induction and the enhancement effect in the retinoic acid-induced neurogenesis.

Date of Award	2021
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	King Lau CHOW (Supervisor)