MAFB is a member of the large MAF transcription factor family (cMAF, MAFA, MAFB, NRL), all of which share a transcriptional activation domain at their N termini. The large MAF proteins regulate terminal differentiation in a variety of tissues, such as the bone, brain, kidney, lens, pancreas and retina, and they appear to have specific and non-redundant functions. In hematopoietic cells, MAFB is expressed in the monocyte lineage, where the lack of MAFB and cMAF cause differentiated macrophages to self-renew without malignant transformation. MAFB also controls osteoclastogenesis, contributes to renal development, where its absence affects podocyte morphology and function, and modulates chondrocyte and pancreatic cell differentiation.
We have previously demonstrated that MAFB is the transcription factor-encoding gene with the highest differential expression between pro-inflammatory and anti-inflammatory human macrophages, and that MAFB critically contributes to the expression of a large percentage of the paradigmatic anti-inflammatory M-MØ-specific genes, including genes that code for proteins with known anti-inflammatory activity like IL10, HTR2B, CCL2 and CD163L1. Therefore, MAFB is critical for the acquisition of an anti-inflammatory activity of human macrophages.
At the pathological level, heterozygous mutations of MAFB are responsible for a rare disease (Multicentric Carpo Tarsal Osteolysis, MCTO, MIM # 166300), a skeletal disorder characterized by progressive bone resorption, as well as for a small percentage of cases Duane Retraction Syndrome (DRS, MIM #617041), characterized by aberrant extraocular muscle innervation and inner-ear defects. Besides, aberrant expression of MAFB characterizes Dupuytren’s cords, a palmar fibromatosis found in Dupuytren's disease (MIM #126900) patients which causes a flexion contracture of the hand.
Given the existence of all these MAFB-related pathologies, our group aims at characterizing the molecular signature of macrophages from MCTO and DRS patients, identifying the range of MAFB target genes in fibroblasts derived from Dupuytren’s cords, and assessing the influence of MAFB MCTO mutations in the generation of monocyte-derived human osteoclasts.