Introduction

The orchestration of cell movement, proliferation and differentiation in a developing embryo is an amazing accomplishment. Many different biochemical signals must be sent and received at the appropriate time and location to guarantee healthy progeny. Our lab is interested in understanding how these signals manifest themselves, and the model organism we use is the mouse. Primarily, we have focused on a family of receptor tyrosine kinases (the platelet derived growth factor receptors, PDGFRα and PDGFRß) that play important roles in both mammalian development and disease.

One set of projects investigates the function of the PDGFRα at various stages of embryonic development. Mutagenesis in mice has shown that the a receptor is required for the proper development of a diverse array of cells including: oligodendrocytes, chondrocytes, alveolar smooth muscle cells, and neural crest cells (NCCs), as well as several other cell types. We are currently investigating the mechanism by which the PDGFRα influences the behavior of these cells during development, and we have concentrated our research on the NCC lineage. (NCCs are a migratory cell type that can differentiate into neurons, chondrocytes, and pigment cells.) By generating a tissue specific deletion of the PDGFRα gene (conditional mutagenesis), we have been able to study the effects of loss of this protein in NCCs, bypassing early embryonic lethality and demonstrating a direct requirement for this receptor in this cell type. Mice with this tissue specific deletion die at birth due to a cleft palate and heart abnormalities, two very common, human birth defects. We are presently studying how these defects in PDGF signaling result in aberrant NCC development. Future projects in the lab will focus on identifying what signals are upstream and downstream of the PDGFRα in NCCs as well as look at these same pathways in other PDGFRα dependent cell lineages.

A second interest in the lab is the role of PDGFRß signal transduction in vascular smooth muscle cell (VSMC) development. (VSMCs are the major support cells of the blood vessel and have been implicated in the progression of atherosclerosis.) We have generated a panel of mice that have specific disruptions in PDGFRß signal transduction. These mice are now being used to identify the key signaling molecules in VSMC development in vivo. In addition, several of the mouse lines exhibit vascular abnormalities including, a proliferative retinopathy, heart fibrosis, and glomerulosclerosis, providing a potential experimental model for these diseases. To expand this project, we will identify genes that are key during VSMC development and determine how these pathways are influenced by PDGFRß signaling.

By using the mouse as a model system we are able to apply the tools of genetics, biochemistry, and embryology to unravel the key signaling molecules in development. Understanding these principles will enable us to define the pathways that become disrupted in human birth defects and disease.