Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects

• Published in: Frontiers in cell and developmental biology 2022-08, Vol.10, p.981893-981893
• Main Authors: Patel, Shaili D, Anand, Deepti, Motohashi, Hozumi, Katsuoka, Fumiki, Yamamoto, Masayuki, Lachke, Salil A
• Format: Article
• Language: English
• Subjects: Cell and Developmental Biology; development; epithelium; lens; MAFG; MAFK; transcription
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2022.981893

Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows : compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly, : double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens in : animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally, : lenses exhibit abnormal distribution of F-actin near the "fulcrum" region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5 : lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g., , , , , , ) were mis-expressed in : lenses. Further, the congenital cataract-linked extracellular matrix peroxidase was significantly overexpressed in : lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptor to be reduced in : lenses. This likely contributes to the : multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors.