The maf oncogene was originally identified as the transduced cellular component of the acutely transforming avian retrovirus, AS42. The murine family of basic/zipper transcription factors that are structurally related to the original v-Maf oncoprotein fall into three categories, designated the large or small Maf family members and the CNC proteins. The large Maf proteins (c-Maf, NRL and MafB) have a typical bZip protein structure (including trans-activation domains), while the small Maf proteins (MafK, MafF and MafG) consist essentially of only a leucine zipper and basic DNA binding domain. In contrast to previous studies which erroneously concluded that the small Maf proteins are present in all animal tissues, these investigators have recently found that MafK and MafG are both highly tissue-restricted in their expression patterns during murine embryogenesis. The small Maf proteins heterodimerize with both large Maf molecules as well as five currently known CNC (Cap-N- Collar) family members (p45 NF-E2, Nrfl, Nrf2, Bachl and Bach2) to bind to specific regulatory sites in DNA. CNC homodimers typically bind poorly to Maf recognition elements (MAREs or NF-E2 sites), while heterodimers consisting of a small Maf protein and a CNC family partner generate trans-activating DNA binding proteins. In contrast to the inactivity of CNC homodimers, homo- or heterodimer formation between small Maf family proteins leads to formation of powerful repressors. Thus small Maf proteins acting alone negatively regulate gene expression, while when acting in collusion with a large Maf or CNC partner, they activate transcription. It is proposed to investigate the developmental genetics of the small maf family genes through execution of four specific aims in this study: First, the investigators will analyze the individual and combinatorial genetic and developmental effects of germ line ablation of the three small maf genes and determine their embryonic and adult developmental expression profiles as well as their null mutant phenotypes; second, they will generate mice which express only single small Maf proteins to test a newly emerging evolutionary hypothesis; third, they will map and then clone a recently identified lethal genetic modifier of mafG; and fourth, they will isolate and then functionally characterize murine YAC recombinants encoding the small maf genes, using them for in vivo rescue of specific small maf loss of function mutations and phenotypes.
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