Genetic disruption of zebrafish mab21l1 reveals a conserved role in eye development and affected pathways

Abstract

Background The male‐abnormal 21 like (MAB21L) genes are important in human ocular development. Homozygous loss of MAB21L1 leads to corneal dystrophy in all affected individuals along with cataracts and buphthalmos in some. The molecular function and downstream pathways of MAB21L factors are largely undefined. Results We generated the first mab21l1 zebrafish mutant carrying a putative loss‐of‐function allele, c.107delA p.(Lys36Argfs*7). At the final stages of embryonic development, homozygous mab21l1c.107delA fish displayed enlarged anterior chambers and corneal thinning which progressed with age. Additional studies revealed increased cell death in the mutant corneas, transformation of the cornea into a skin‐like epithelium, and progressive lens degeneration with development of fibrous masses in the anterior chamber. RNA‐seq of wild‐type and mutant ocular transcriptomes revealed significant changes in expression of several genes, including irf1a and b, stat1, elf3, krt17, tlr9, and loxa associated with immunity and/or corneal function. Abnormal expression of lysyl oxidases have been previously linked with corneal thinning, fibrosis, and lens defects in mammals, suggesting a role for loxa misexpression in the progressive mab21l1c.107delA eye phenotype. Conclusions Zebrafish mab21l1 is essential for normal corneal development, similar to human MAB21L1. The identified molecular changes in mab21l1c.107delA mutants provide the first clues about possible affected pathways.

CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements

“…To further study the cornea defects, 30-dpf foxc1a ∆CED1−3 mutant sections were stained for N-cadherin (cdh2) that marks corneal epithelium and endothelium, and corneal keratan sulfate proteoglycan (CKS), which is a marker for corneal stroma [ 31 ]. Cornea epithelium at 30-dpf is composed of several layers of epithelial cells, an acellular and well-ordered stroma, and an endothelial monolayer (Fig.…”

MAB21L1 promotes survival of lens epithelial cells through control of αB-crystallin and ATR/CHK1/p53 pathway

“…Mutations in human Mab21L1 gene causes aberrations in lens ectoderm morphogenesis and lead to congenital cerebellar, ocular, craniofacial and genital (COFG) syndrome [ 101 , 102 ]. The ocular abnormalities include microphthalmia, coloboma and cataracts [ 7 , 9 ]. Similar to human mab21L1 gene mutations, Mab21L1-deficient mice display severe cell-autonomous defects in lens placode invagination due to impaired cell proliferation and survival [ 5 ] and other deficiency [ 6 , 101 ].…”

“…Later it was found that Mab21L1 is a lens lineage-specific transcription factor [100]. It has an important role in regulating lens development [5,[7][8][9]11]. Mutations in human Mab21L1 gene causes aberrations in lens ectoderm morphogenesis and lead to congenital cerebellar, ocular, craniofacial and genital (COFG) syndrome [101,102].…”

“…The male abnormal gene family 21 (mab21), was first identified in C. elegans [1]. Since its identification, mab21L1 gene was found to control development of both eye and brain [2][3][4][5][6][7][8][9]. Moreover, it also has a role in regulating axis and dorsal-ventral patterning as well as heart and liver development [3,4,10].…”

“…Moreover, it also has a role in regulating axis and dorsal-ventral patterning as well as heart and liver development [ 3 , 4 , 10 ]. Mutations of the human mab21L1 gene cause numerous ocular diseases including ocular coloboma, microcornea and cataract, neural defects, skeletal dysplasia and intellectual disability [ 7 , 9 , 11 ]. However, the functional mechanism of the mab21L1 gene remains largely unknown [ 8 , 12 ].…”