…there isn’t any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease. -William Harvey, 1657
Our research goals are to understand the causes of congenital skeletal disorders and, in the process, gain deeper insights into skeletal development. We use human genetics as a starting point for discovery and then model human disease using patient-specific cells, mouse genetics, and avian experimental embryology. By studying rare events in human development, we are addressing these outstanding questions in skeletal biology:
How are cell fate decisions made during skeletal development?
Dividing chondrocyte during metaphase (left) and anaphase (right).
During skeletal development, mesenchymal progenitor cells make the choice to self-renew or terminally differentiate into osteoblasts, chondrocytes, tenocytes, or ligamentocytes. We are studying the molecular regulators in skeletal progenitor cells that 1) act as a switch between self-renewal and differentiation and 2) specify cell lineage choice. We are identifying previously unknown cell fate determinants using patient-specific cells and mouse models for human skeletal disorders such the FGFR2-disorder Bent Bone Dysplasia syndrome and the RUNX2-disorder Cleidocranial Dysplasia.
How are bones and tendons linked during development?
MicroCT renderings of a mouse skull (left) with a GFP-tendon reporter overlay (right).
Tendons facilitate body movement by delivering high tensile forces from muscle to bone. Tendon and bone have vastly different elastic moduli and their attachment requires a transitional structure called the enthesis, which reduces stress concentrations across the soft-hard tissue interface. The enthesis is a continuously graded tissue made of tendon, fibrocartilage, and mineralized fibrocartilage. Remarkably, the graded enthesis arises from regional differentiation of a bipotent Scx+/Sox9+ progenitor pool into either tenocytes or chondrocytes. We are revealing a novel mechanism that spatially resolves Scx+/Sox9+ progenitor bipotency during enthesis morphogenesis using a mouse models for the FGFR2-disorder Lacrimo-auriculo-dento-digital (LADD) syndrome and the Jagged1-disorder Alagille syndrome.
How are joints established and maintained?
Chick knee joint following RCAS mediated expression of GFP (left) and the Bent Bone Dysplasia mutation (right).
Joints connect articulating bones within the vertebrate skeleton. While all joints share this role, their morphologic diversity produces a broad range of mechanical possibilities, which are controlled by the composition of joint connective tissues and joint shape. There are three major classes of joints: freely movable synovial joints, slightly movable cartilaginous joints, and immovable fibrous joints. The distinct morphologic and histogenic characteristics of each joint class are established during embryonic development, yet the connection in the molecular regulation is relatively unknown. Human skeletal disorders with enhanced FGF signaling exhibits abnormalities in all joint types. Up to this point, the role of FGF signaling in joint development has been largely defined by studies focused on fibrous joints in the skull. We are defining the role of FGF signaling in synovial and cartilaginous joint development using avian embryology and mouse models for Bent Bone Dysplasia and LADD syndromes.
How is skeletal patterning and growth coordinated with tissues of the nervous system?
MicroCT renderings of skulls from the Bent Bone Dysplasia mouse (left) and control (right).