Lefebvre Laboratory

Skeletal and brain diseases occur in many forms with variable degrees of severity. At one end of the spectrum are rare congenital malformations severely reducing life expectancy or quality of life. At the other end are adult-onset degenerative diseases like osteoporosis, osteoarthritis, and dementia. Despite some recent developments, treatment options and cures are still missing or insufficient for most of these diseases. Research is needed to find novel strategies to prevent, effectively treat, or cure these diseases.

Research in the Lefebvre Lab focuses on advancing the fundamental understanding of the genetic mechanisms whereby specific cell types acquire the unique and challenging functions of developing highly sophisticated and specialized structures as the skeleton and brain in early life, and keeping these structures healthy throughout life. These cells include skeletal progenitor/stem cells, chondrocytes, osteoblasts, and neocortical neurons.

The laboratory has a long track record of deciphering how members of SOX transcription factor family drive the genetic programs that determine the identity and differentiated activities of these cells and how these factors are themselves controlled by regulatory networks. In addition to these fundamental science projects, the Lefebvre Lab also works on translational projects aimed at uncovering the mechanisms whereby de novo, heterozygous mutations in SOX genes lead to SOXopathies; that is, a family of rare human developmental syndromes impacting various systems, including the skeleton and brain. The main goal of the lab is to find ways to treat children born with these diseases and give them and their loved ones the best possible chances at life.

Experimental approaches in the lab include state-of-the-art techniques and include mouse models; cell reprogramming and differentiation assays in vitro; high-throughput sequencing approaches for chromatin, RNA, and protein; and various software programs for large data mining and analysis.

Project Highlights

• Roles of SOX8 and SOX9 (SOXE proteins) in cartilage cell specification, growth plate cartilage formation and closure, and skeletal malformation diseases, including chondrodysplasias and dwarfism
• Roles of SOX8 and SOX9 in articular cartilage development and adult homeostasis, and in degenerative joint diseases, including osteoarthritis
• Roles of SOX4 and SOX11 (SOXC proteins) in skeletal stem/progenitor cells in development and adulthood and in skeletal dysplasias, such as cleft palate and craniosynostosis
• Roles of SOX4 and SOX11 in bone formation in development and adult homeostasis, and in such diseases as bone fracture healing and osteoporosis
• Identification of developmental diseases due to mutations in SOX genes (i.e., Lamb-Shaffer syndrome, which is due to SOX5 mutations and is characterized by global developmental delay and intellectual disability; and a newly discovered neurodevelopmental syndrome associated with mild dysmorphism, which is due to SOX4 mutations), the study of underlying molecular mechanisms, and the search for therapeutic treatments
• Structure/function analysis of SOX proteins, with emphasis on discovering molecular partners and regulators of the proteins and how missense mutations in critical SOX protein domains cause skeletal, neurodevelopmental, and other diseases