 |
Véronique Lefebvre, Ph.D.Associate StaffDepartment of Cell Biology/ NC-10 |
Transcriptional control of cell fate and differentiation
My laboratory is primarily interested in deciphering transcriptional mechanisms involved in the control of cell fate and differentiation during skeletogenesis. Most of our projects focus on Sox transcription factors. These proteins are encoded by a family of twenty genes in most vertebrates. Their common feature is an Sry-related high-mobility-group box (Sox) DNA-binding domain. Some Sox proteins also harbor a transactivation domain, a dimerization domain, and other protein-interaction and regulatory domains. As a whole, the Sox family has critical roles in determining cell fate and differentiation in virtually all lineages, including pluripotent and multipotent stem cells. Mutations within and around Sox genes cause complex malformation syndromes in humans, such as XY sex reversal, skeletal dysplasia, and common arterial trunk. Moreover, changes in their gene expression show strong association with cancer progression and the development of other acquired diseases.
Research in our laboratory in recent years has contributed to demonstrate that Sox5, Sox6, and Sox9 form a trio that is required for chondrogenesis. Deficiency in Sox9 or in the redundant Sox5 and Sox6 proteins leads to severe skeletal malformations in the mouse. The cartilage templates of most bones fail to form or poorly develop. Consequently, the mice are dwarfs and their bones and joints are very abnormal. The Sox trio is needed and sufficient to activate the genes for all major structural components of the cartilage extracellular matrix. The Sox5/Sox6 proteins have no transactivation domain, but their binding to DNA is required to allow Sox9 to bind efficiently to adjacent sites on cartilage-specific enhancers and thereby to activate gene transcription. Our current projects focus on determining the mechanisms whereby the three proteins cooperate with each other and on further deciphering their roles in multiple aspects of the chondrocyte differentiation program. In a separate project, we are studying the transcriptional mechanisms that direct Sox9 expression in the chondrocyte lineage. We have identified two enhancers far upstream of the gene. We are using gene targeting and transgenesis approaches to determine to which extent these enhancers are needed for Sox9 expression. We are also using genetic and biochemical approaches to identify the transcription factors that mediate the activity of these enhancers. We anticipate that these factors are key determinants of chondrocyte fate and differentiation.
Other research projects in the laboratory focus on the roles and modes of regulation of Sox4, Sox11, and Sox12. These three proteins form the SoxC group. We have shown that they share similar DNA-binding and transactivation properties and are co-expressed in multipotent mesenchymal and neural cells in vivo and in vitro. Based on these data, we have hypothesized that the three genes could have largely redundant functions. To test this hypothesis, we generated mice harboring conditional null alleles for each SoxC gene. Confirming our hypothesis, we recently published that the combined inactivation of the SoxC genes has dramatic consequences on mouse embryogenesis. It does not affect cell proliferation or lineage specification, but leads to massive apoptosis of neural and mesenchymal cells. As a result, embryos developmentally arrest and die in the early steps of organogenesis. We have demonstrated that the SoxC proteins mediate their functions in neural and mesenchymal precursors at least in part by directly activating the gene for Tead2, a transcription factor involved in the control of cell growth and survival in physiological processes and cancer downstream of the Hippo pathway. Our current focus in this project is to find the additional targets of the SoxC proteins in mesenchymal cells and to study the specific roles of the SoxC genes in skeletogenesis.
Overall, 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 and other inherited and acquired human diseases.
Smits P, Dy P, Mitra S, Lefebvre V. Sox5 and Sox6 are needed to develop and maintain source, columnar and hypertrophic chondrocytes in the cartilage growth plate. J Cell Biol 164:747-758 (2004).
Lefebvre V, Smits P. Transcriptional control of chondrocyte fate and differentiation. Birth Defects Research C Embryo Today 75:200-212 (2005).
Dumitriu B, Patrick MR, Petschek JP, Cherukuri S, Klingmüller U, Fox PL, Lefebvre V. Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development. Blood 108:1198-1207 (2006).
Lefebvre V, Dumitriu B, Penzo-Méndez A, Han Y, Pallavi B. Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 39:2195-2214 (2007). PMCID: PMC2080623.
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). PMCID: PMC2396431.
Han Y, Lefebvre V. L-Sox5/Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer. Mol Cell Biol 28:4999-5013 (2008). PMCID: PMC2519711.
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). PMCID: PMC186032.
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 10.1038 / 1008 (2010). PMCID: PMC196876.
Harley V, Lefebvre V. Twenty Sox, twenty years. Int J Biochem Cell Biol 42:376-377 (2010).
Lefebvre V. The SoxD transcription factors - Sox5, Sox6, and Sox13 - are key cell fate modulators. Int J Biochem Cell Biol 42:429-432 (2010). PMCID: PMC2826538.
Penzo-Méndez AI. Critical roles for SoxC transcription factors in development and cancer. Int J Biochem Cell Biol 42:425-428 (2010). PMCID: PMC196878.