The Missing Bone

that leads to sequential expression of other transcription factors and of phenotype-specific genes (Rawls and Department of Bone Biology and Osteoporosis Research Olson, 1997). Homology searches for HLH factors that play a similar role in adipocyte, osteoblast, or chon-Merck Research Laboratories West Point, Pennsylvania 19486 droblast differentiation have not been successful (negative data are rarely published). However, a key regulatory transcription factor in adipocyte differentiation, belonging to the nuclear receptor family (peroxisome prolifera-The mineralized skeleton was essential for the evolution tor activated receptor ␥2 or PPAR␥2; Tontonoz et al., of terrestrial vertebrates since it provided an ample 1994), was discovered three years ago. A transcription source of calcium and phosphate and facilitated loco-factor that plays a key role in osteoblast differentiation motion on solid ground. Bone also provides protection is described in this issue of Cell. This factor is CBFA1, from external injury for the brain and spinal cord. In a member of the core-binding factor family, also known addition, it houses and interacts with the bone marrow, as PEBP2␣A (for polyoma enhancer binding protein) and supporting hematopoieses. Another crucial mechanical as AML3 (for acute myeloid leukemia). function of bone in land vertebrates is breathing, and CBFA belongs to the Runt domain gene family, homol-a severely compromised skeleton causes immediate ogous to the Drosophila melanogoster pair-rule gene postnatal death. runt that plays a role in the formation of the segmented Embryologically, we recognize two types of bone. In-body pattern as well as in sex determination and in tramembraneous bone is formed directly by bone cells the development of the nervous system (Ogawa et al., within connective tissue. It originates from the branchial 1993). The ␣ subunit of these heterodimeric transcription arches and gives rise to the bones of the skull and the factors binds to DNA via the Runt domain when paired face. The rest of the skeleton is generated by bone with the ␤ subunit, called CBFB/PEBP2␤, which does replacement of a cartilage anlage through the process not directly interact with DNA. The consensus DNA bind-of endochondral ossification, where vascular invasion ing sequence is PuACCPuCA, originally identified as an is followed by the deposition of bone on mineralized enhancer in polyoma virus and murine leukemia virus, cartilage, which is subsequently removed. This bone is but also present in many T cell–specific genes, TCR␣, derived from the somites that contain multipotent cells-␤,-␦,-␥, CD3⑀, as well as in genes encoding the …