Our laboratory uses multidisciplinary approaches to decipher molecular mechanisms implicated in the control of several important developmental and physiological processes. We specifically focus on uncovering roles for Sry-related high-mobility-group box (Sox) transcription factors in determining cell fate and differentiation in skeletogenesis and erythropoiesis. Using gene inactivation strategies in the mouse and complementary approaches, we discovered that Sox5 and Sox6 form a chondrogenic trio with Sox9. They are required to develop cartilage primordia, the embryo primary skeleton, and cartilage growth plates, the drivers of skeletal growth and endochondral ossification. They activate cartilage matrix genes and stimulate chondrocyte proliferation and maturation. Further, we uncovered that Sox6 has critical, unique roles in definitive erythropoiesis. It cell-autonomously enhances the ability of erythropoietin signaling to stimulate erythroid cell survival and proliferation. It also promotes erythroid cell maturation and thereby ensures erythrocyte long-term survival. We recently started studies on the closely related Sox4, Sox11, and Sox12 factors. We found that these factors have essential roles in various cell lineages and thereby in the development of multiple organs, including the skeleton. Our research thus advances knowledge of the transcriptional control of key developmental and physiological processes and thereby provides solid foundations for understanding the molecular basis of skeletal, hematological, and other inherited and acquired human diseases.
We recently showed that Sox4, Sox11, and Sox12 exhibit similar DNA-binding and transactivation functions and display overlapping expression patterns in the mouse embryo. Through generation of mice lacking either one or all SoxC genes, we have uncovered that the SoxC genes act in redundancy to ensure neural and mesenchymal cell survival in the early embryo and are thereby essential for organogenesis. Specific inactivation of the SoxC genes in skeletogenic mesenchyme leads to severe skeleton patterning, growth, and maturation defects, and we are currently investigating how SoxC proteins control key genes and proteins within the complex molecular networks that regulate skeletogenesis. In other recent work, we generated a new, inducible gene inactivation strategy and used it to study the importance of Sox9 beyond its well-known roles in specification and differentiation of early chondrocytes. We have made the paradigm-shifting discovery that Sox9 maintains critical roles through the successive stages of the chondrocyte maturation process in the cartilage growth plate, a specialized structure driving skeleton growth and ossification. Sox9 maintains chondrocyte proliferation and generates cell hypertrophy, key features of functional growth plates. Moreover, Sox9 is necessary to maintain the lineage fate of chondrocytes and thereby prevents them from becoming osteoblastic (bone-forming cells). We are currently investigating the mechanisms whereby Sox9 fulfills distinct functions at different stages of chondrogenesis. Overall, these and other results from our research illuminate understanding of major mechanisms underlying skeletogenesis and take us closer to finding causes and treatments for highly prevalent skeletal malformation and degeneration diseases in humans.
Radhika Atit, Ph.D., Department of Genetics, Case University
Dy P, Penzo-Méndez A, Wang H, Pedraza CE, Macklin WB, Lefebvre V. The three SoxC proteins – Sox4, Sox11, and Sox12 – exhibit overlapping expression patterns and molecular properties. Nucleic Acids Res 36, 3101-3117 (2008).
Dy P, Smits P, Silvester A, Penzo-Méndez A, Dumitriu B, Han Y, de la Motte CA, Kingsley DM, Lefebvre V. Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage. Dev Biol 341, 346-359 (2010).
Bhattaram P, Penzo-Méndez A, Sock E, Colmenares C, Kaneko KJ, Vassilev A, DePamphilis ML, Wegner M, Lefebvre V. Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nat Commun 1, 9 (2010).
Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock R.T., Lefebvre V. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation or growth plate chondrocytes. Dev Cell 22, 597–609 (2012).