Jan Christian

Professor - Cell and Developmental Biology

Molecular Basis of Vertebrate Embryonic Patterning

Cell-cell signaling molecules, such as bone morphogenetic proteins (BMPs), play critical roles in specifying cell fate during vertebrate embryogenesis. We are studying two aspects of BMP function during early development: regulation of BMP activity by proteolysis and the role of BMPs in hematopoietic stem cell differentiation.

BMPs, like all TGF-ß family members, are synthesized as inactive precursors that must be cleaved to yield the active, mature protein dimer. ProBMP-4 is unusual in that it is sequentially cleaved at two sites within the inactive, prodomain portion of the molecule. This ordered proteolysis regulates the activity and signaling range of the mature ligand. We are generating and analyzing mice carrying knock in point mutations in the upstream cleavage site to test the hypothesis that this site is used in a tissue-specific fashion to regulate BMP activity and to study its relevance for normal embryonic patterning. Analysis of BMP4 maturation in Xenopus oocytes suggests that sequential cleavage regulates endocytic trafficking and thus determines the half life and range of action of mature BMP-4. To further test this hypothesis, we are collaborating with Dr. Marcel Wehrli to study the cell biology of regulated cleavage in Drosophila embryos. This enables us to visualize BMP trafficking across tissues and in mutants defective for different aspects of endocytic trafficking. In addition to understanding how sequential cleavage of proBMP4 regulates its activity, we are studying the broader question of how PC-mediated maturation of other TGF-ß family members is regulated.

A second goal of research in our laboratory deals with role of BMPs in hematopoietic stem cell differentiation. We have shown that proper regulation of BMP signaling in non-hematopoietic cells is critical for normal primitive erythropoiesis. Inhibition of BMP signaling in ectodermal cells of Xenopus embryos induces erythroid precursors to undergo apoptotic cell death while upregulation of BMP leads to the development of large numbers of immature macrophages and a loss of red blood cells. Our studies suggest that BMPs are required to activate expression of a secreted protein that regulates survival and lineage choice of hematopoietic stem cells. Current efforts are directed toward identifying gene products that function in parallel to our downstream of BMPs during erythropoiesis.

To contact Dr. Christian directly: christia@ohsu.edu