Dr. Benoit de Crombrugghe
Distinguished Senior Lecturer
The University of Texas M. D. Anderson Cancer Center
Department of Genetics
- Cell differentiation
- Transcription factors
My laboratory is interested in the molecular and genetic mechanisms that control the fate of cell types that are derived from mesenchymal cell precursors, specifically chondrocytes and osteoblasts. Our central hypothesis is that specific transcription factors control the differentiation pathways for each of these cell types. Our aim is to identify these transcription factors, understand how they function to control broad genetic programs, and determine how their expression or activity responds to major cellular signaling pathways.
We have shown that the transcription factor SOX9 is required at multiple steps of the chondrocyte differentiation pathway. SOX9 is also needed for the expression of two other members of the SOX family, SOX5 and SOX6, which in turn are required at a specific step in the pathway, that of overt differentiation of chondrocytes. In addition to its essential role in chondrogenesis, SOX9 also controls the cell fate of several other cell lineages in endocardial cushions, in primordia of the pancreas, in the cranial neural crest, in the male gonad. We hypothesize that other transcription factors provide the additional specificity to SOX9 in these different lineages. Our present work is focusing on the biochemical mechanisms by which SOX9 exerts its different roles during chondrogenesis and how the 3 SOX proteins cooperate in control of chondrogenesis. We have also established exciting links between SOX9 and signaling molecules that are known to influence chondrocyte differentiation in vivo. For instance, SOX9 is a target of signaling by the parathyroid hormone-related peptide. In addition, fibroblast growth factors (FGFs) increase the expression of SOX9 in tissue culture cells. Since achondroplasia, the most common form of dwarfism in humans, is caused by activating mutations in FGF receptor 3, we have postulated that SOX9 has a role in this disease.
We have also recently identified a novel transcription factor called Osterix that is specifically expressed in osteoblasts and is completely required for osteoblast differentiation. In mice that lack this transcription factor, osteoblast differentiation and bone formation do not occur. This factor controls a broad array of osteoblast-specific genes and acts downstream of another key factor for osteoblast differentiation called Runx2. In addition to its role as the major effector of the osteoblast program, Osterix is also a negative regulator of the chondrocyte lineage. Our present work examines the mechanisms by which Osterix exerts these effects.