The Missing Bone

Abstract

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 locofactor 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. Inbody 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 en-capable of differentiating into muscle, dermis, and cartizymes myeloperoxidase, neutrophil elastase, and gran-lage. Experimental approaches have identified pluripozyme B, and in several genes encoding cytokines and tent mesenchymal cells that have myogenic, chondrotheir receptors GM-CSF, IL-3, and CSF-1. genic, and adipogenic potential, raising the question of Three CBFA genes have been identified: CBFA1/ signals and regulatory pathways that determine commit-PEBP2␣A/AML3, CBFA2/PEB2␣B/AML1, and CBFA3/ ment to one of these lineages. In vivo, the cues seem PEBP2␣C/AML2...

Complete absence of rib ossification, micrognathia and ear anomalies: extreme expression of cerebro-costo-mandibular syndrome?

“…24,25 Cfba1 is a transcription factor of the runt family and essential for the activation of osteoblast differentiation. 26,27 Knockout mice for Cbfa1 showed a complete lack of both intramembraneous and endochondral ossification. However, the clinical features in the human homologue of heterozygous loss of Cbfa1, cleidocranial dysostosis, differ widely from the features in the present case, 28 making it a less likely candidate gene.…”

Groucho proteins: transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates

“…During Drosophila development, Runt and Lozenge play roles in segmentation, neurogenesis, sex-determination, and eye development (for review, see Duffy and Gergen 1994;Daga et al 1996). In mammals, family members are essential for bone development and hematopoiesis (Speck and Terryl 1995;Okuda et al 1996;Ducy et al 1997;Komori et al 1997;Otto et al 1997;Rodan and Harada 1997). In humans, mutation or translocation of the AML1 and CBFA1 genes are a common occurrence in several forms of leukemia and lymphoma in adults and children, or are responsible for the inherited skeletal disorder cleidocranial dysplasia, respectively (Lo Coco et al 1997;Mundlos et al 1997).…”

“…For example, the Drosophila Runt protein represses hairy and even-skipped expression, but activates the expression of fushi-tarazu and Sex-lethal (Duffy and Gergen 1994;Aronson et al 1997). The mammalian Runt domain proteins have only been characterized as activators of a large number of target genes in blood cells and bone (Speck and Terryl 1995;Rodan and Harada 1997), although the recent demonstration of repressor activity for these proteins may lead to the identification of repressed targets (Aronson et al 1997). However, in contrast to Dorsal, the Runt domain proteins appear to function intrinsically as transcriptional repressors, and to act only as activators in a context-dependent manner ( Fig.…”

Characterization of a Novel KRAB/C2H2Zinc Finger Transcription Factor Involved in Bone Development

“…1-3) along with the identification of Runx2/Cbfa-1/Osf2 (Runt domain factor 2/core binding factor ␣-1/osteoblast specific factor 2; reviewed in Ref. 4) as a master gene for osteogenesis (5) has established a template for osteogenic differentiation. However, the molecular mechanisms linking the osteogenic effects of BMPs and Runx2 and the expression of a bone matrix by osteoblastic cells are still largely unknown.…”