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Salil Lachke, Smriti Agrawal, Atul Kakrana, Christine Dang, Stephanie Waters, Abhyudai Singh, Hozumi Motohashi; Identification of small MAF family transcription factors MafG and MafK associated with cataract. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3191.
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© ARVO (1962-2015); The Authors (2016-present)
The MAF (musculoaponeurotic fibrosarcoma) gene family encodes basic leucine zipper transcription regulators that are classified into “large” and “small” MAF subgroups. Although mutations in the large MAF family gene MAF (c-MAF) are associated with human congenital cataracts, the function of the small MAF subgroup proteins MafG, MafK, and MafF in the lens remains uncharacterized.
We used iSyTE (integrated Systems Tool for Eye gene discovery), a bioinformatics resource-tool that predicts genes associated with lens development and cataract, to identify the small Maf family gene MafG as a potential regulator in the lens. To test this prediction, we focused on characterization of mouse models carrying targeted mutant alleles of small Maf genes. We performed in situ hybridization, immunofluorescence and gene expression profiling by mouse Illumina WG-6 v2.0 Expression BeadChip microarrays to characterize the lens defect exhibited in small Maf mutant mice.
Using in situ hybridization, we confirmed expression of MafG in the mouse lens beginning as early as embryonic day E10.5. We generated mice that were MafG-/-, MafK-/- or MafG-/-:MafK+/- compound mutants and initiated a characterization of lens defects in these animals. We find that MafG-/-:MafK+/- compound mutants exhibit severe lens defects and develop pre-senile cataract at age 4 months. To identify the likely primary targets of these regulators, we performed whole genome transcript profiling by microarrays on lenses from MafG-/-:MafK+/- mutant mice at age 2 months, well before the detection of an obvious lens defect. Our initial analysis indicates that expression of the heat shock protein encoding gene Hspb1 (Hsp27) and a novel tetratricopeptide repeat domain 27 protein encoding gene Ttc27 is down-regulated in MafG-/-:MafK+/- compound mutant lenses. Interestingly, Hspb1 (Hsp27) protein is found to interact with lens crystallin proteins Cryaa, Cryab and Crybb2 and is also found to be downregulated in lenses carrying homozygous null mutations of the RNA granule component gene Tdrd7, deficiency of which in mouse or human causes cataract.
Collectively, our data has identified and characterized a new role for the small Maf transcriptional regulators MafG and MafK in controlling lens fiber cell gene expression, and demonstrated that deficiency of these proteins in mouse results in lens defects and cataract.
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