Kreisler (kr) is a classical mutation that affects morphologic segmentation of the hindbrain, expression of certain Hox genes and paracrine signaling molecules, and development of the otic vesicle. Recent experiments from our laboratory have shown that kr encodes a transcriptional regulator similar, but not identical, to vMaf, a basic domain/leucine zipper (bZIP) protein previously identified as an oncogene in a chicken retrovirus. In chickens, members of the Maf family are widely expressed, and will heterodimerize extensively with Fos or Jun to produce bZIP complexes with altered binding specificities. The potential target genes of vMaf are not known, but genetic and gene expression studies in mice suggest that Kreisler is a positive regulator of the Fgf3 gene. Although kr has a specific role during embryogenesis, previous studies of other Maf proteins have suggested that many function primarily in adult tissues to modulate the response of genes normally regulated by the AP-1 complex. To help determine the biologic function and repertoire of different Kreisler/Maf family members, in situ hybridization studies will be performed on mouse embryos for the four Kreisler/Maf genes already isolated, and molecular cloning experiments will be initiated to isolate new members from mouse genomic DNA and mouse embryo RNA. Regulatory regions for genes that lie genetically downstream of Kreisler will be examined for binding of recombinant Kreisler protein in vitro, and reporter constructs will be designed to test these sites in vivo. The ability of Kreisler to activate potential in vivo targets, Fgf3, Hoxb3, and Krox20, will be investigated by ectopic expression of Kreisler in transgenic animals. Finally, the potential role that Kreisler/Maf genes play in oncogenesis will be studied by generating a knockout allele of Maf, and determining the susceptibility of Maf mutant animals to vFos- induced tumor formation.
