The transcription factor c-Maf is a member of the large Maf family, members of which possess transactivation and bZIP domains. c-Maf plays an important role in lens formation, Tlymphocyte differentiation, hypertrophic chondrocyte differentiation, and kidney development in mouse embryos. However, because homozygous deletion of c-Maf in C57BL/6J mice causes embryonic lethality, the functions of c-Maf in adult mice remain largely uninvestigated. To address this issue, we generated c-Maf floxed (c-Maf fl/fl) C57BL/6J mice and established tamoxifen-inducible c-Maf knockout mice (c-Maf fl/fl ; CAG-Cre-ER TM mice, c-Maf ΔTAM). After tamoxifen injection, adult c-Maf ΔTAM mice showed successful deletion of c-Maf protein and developed severe cataracts; cataracts are also seen in human patients who have mutations in the c-MAF DNA binding domain. Furthermore, adult c-Maf ΔTAM mice exhibited abnormal lens structure and impaired differentiation of lens fiber cells. In summary, we established c-Maf fl/fl and c-Maf ΔTAM C57BL/6J mice, which can be useful animal models for the investigation of c-Maf function in various developmental stages and can also be used as a disease model for cataracts.

The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen (TAM)-inducible c-Maf knockout mice (c-Maf flox/flox ; CAG-Cre-ER TM mice named "c-Maf ΔTAM ") with that of c-Maf flox/flox control mice, 10 days after TAM injection (TAM(10d)). In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin (STZ), 4 weeks before TAM injection. c-Maf ΔTAM mice displayed primary glycosuria caused by Sglt2 and Glut2 downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.

Aymé-Gripp syndrome is an autosomal dominant multisystem disorder. The major clinical features of this syndrome include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. MAF has been identified as a causative gene of the syndrome, and heterozygous variants owing to impairment in glycogen synthase kinase 3 (GSK3)-mediated MAF phosphorylation shows related disorders. However, the underlying mechanisms of these types of disorders in affected individuals remain poorly understood. To explore the underlying mechanisms and discover new phenotypes, a murine model with a Maf mutation on a GSK3 phosphorylation motif, p.Thr58Ile, was generated using CRISPR-Cas9 gene editing. This is a homologous mutation to that in human patients. Our murine model exhibited similar phenotypes to those in humans, such as lens abnormalities, short stature, growth retardation, and abnormal skull morphology. The murine model showed decreased brain volume and malocclusion. Considering the sequencing and genotyping data, our models were successfully generated for the first time (to the best of our knowledge). Therefore, this study offers new and unique functional insights into human and murine MAF and novel clinical values of MAF pathogenic variants associated with changes in the functions of several organs based on a viable murine model.