Genetic control of skeletal morphogenesis.
My laboratory seeks to understand how specific bone elements in the skeleton are formed to acquire their characteristic shape and grow correctly. We focus on the gene regulatory networks controlled by the transcription factors Foxc1 and Foxc2 that guide these developmental processes. Our research activities are divided into the following area:
1. Formation of the skeleton
The mammalian skeleton forms through two developmental processes: intramembranous ossification and endochondral ossification. Intramembranous ossification processes form the flat bones of the skull and occur through the direct differentiation of mesenchymal progenitor cells directly into bone forming osteoblast cells. In contrast, the majority of the skeleton forms through endochondral ossification events whereby mesenchyme progenitor cells transition through a cartilage intermediate, that facilitates growth and patterning, before being replaced by a bony matrix. This developmental pathway is tightly regulated and disruption in its ordered progression can have profound developmental defects to the skeleton. Foxc1 and Foxc2 are critical regulators of both ossification pathways. Our laboratory focuses on the role of Foxc1 and Foxc2 in endochondral ossification. In addition we use genome-wide approaches (ChIP-seq and RNA-seq) to identify genes under the regulatory control of Foxc1 and Foxc2 needed to correctly form the skeleton.
2. Patterning the skeleton
The shape and size of the bone in our skeleton are varied, yet the development processes that form them are similar. We know very little about how specialized bone structures that articulate into joints or allow attachment of tendons and ligaments form. Using conditional knock-out models we have identified roles for Foxc1 and Foxc2 in the formation of bone eminences. These bumps and protrusions are important morphological features that allow movement and their under development can have clinical ramifications, as seen in hip dysplasia. We study how signaling pathways intersect with transcriptional regulatory networks to control formation of these bone protrusions. We also study how mechanical cues guide the formation and patterning of bone structures and the functional consequences of bone-tendon-muscle malformations on movement and locomotion.
3. Transcription networks regulating cell fate decisions.
Changes in gene expression are a hallmark of cell differentiation. Many of such genes expressed will guide cells along this developmental path and will also contribute to the final phenotype. We are interested in understanding how transcription factors act to specify these gene regulatory networks that lead to cell differentiation events. To study these processes we use mouse embryonic stem cells targeted to differentiate towards specific lineages and monitor how changes in gene expression can influence differentiation outcomes.