The c-fos proto-oncogene has been implicated as a central regulatory component of the nuclear response i: o mitogens and other extracellular stimuli. Embryonic stem cells targeted at the c-fos locus have been used i: o generate chimeric mice that have transmitted the mutated allele through the germline. Homozygous mu-1: ants show reduced placental and fetal weights and significant loss of viability at birth. Approximately 40% of the homozygous mutants survive and grow at normal rates until severe osteopetrosis, characterized by foreshortening of the long bones, ossification of the marrow space, and absence of tooth eruption, begins to develop at approximately 11 days. Among other abnormalities, these mice show delayed or absent gametogenesis, lymphopenia, and altered behavior. Despite these defects, many live as long as their wildtype or heterozygous littermates (currently 7 months). These data indicate that c-fos is not required for the growth of most cell types but is involved in the development and function of several distinct tissues. c-fos is a nuclear proto-oncogene expressed in a wide range of tissues (reviewed in Distel and Spiegelman, 1990). It is the cellular homolog of the oncogenes carried by the FBJ and FBR murine osteogenic sarcoma viruses (Curran et al., 1982; van Beveren et al., 1983). The c-fos gene is pat-t of a multigene family that includes fosf3, fra-7 and fra-2; all of these genes share a hydrophobic, leucinerich domain termed the leucine zipper, that mediates pro-&in-protein interactions and a basic region that mediates DNA binding. All of the members of the Fos family are able to form heterodimers with Jun protein family members, with varying degrees of avidity (Halazonetis et al., 1988; Nakabeppu and Nathans, 1989; Abate et al., 1991; Hai et ad., 1991). Fos-Jun heterodimers bind DNA at AP-1 sites, which are cis-acting transcriptional regulatory sequences found in a large number of genes, including those encoding collagenase, interleukin-2, and adipocyte P2 (Farrar et al., 1989; Schijnthal et al., 1988; Distel et al., 1987; Rauscher et al., 1988).

The c-fos proto-oncogene is an immediate-early gene, with a characteristic rapid transcriptional activation in quiescent cells following mitogenic stimulation (Greenberg and Ziff, 1984). c-fos transcription in cultured fibroblasts is induced by many factors, including EGF, PDGF, TPA, and mechanical stimulation (reviewed in Angel and Karin, 1991). Constitutive c-fos expression is seen in a limited number of tissues, however, including amniotic and placental tissue, fetal liver, adult bone marrow and growing bone, and in the developing central nervous system (Miiller et al., 1983; Caubet, 1989). Recent studies in transgenic mice using a bacterial/acZ gene fused to the 5’regulatory region of the c-fos gene indicated that expression in bone is especially prominent in regions undergoing degenerative remodeling (Schilling et al!., 1991; Smeyne et al., 1992).