Jan Christian

The long term goal of our research program is to understand how members of the Transforming growth factor ß (TGFß) and Bone morphogenetic protein (BMP) families regulate embryonic development and adult homeostasis to prevent birth defects and disease. We use Xenopus as a simple vertebrate model system with which to dissect molecular components of signaling pathways and complement these with studies in mouse to examine genetic and biochemical interactions. Our research program has two major foci:

1.  Understanding how point mutations in the prodomain of BMP precursor proteins cause birth defects and iron overload in humans. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the active ligand and a prodomain fragment.  Although the  prodomain lacks signaling activity, it guides ligand folding and influences whether more active BMP heterodimers, or less active homodimers are formed. Our recent discovery that BMP2/7 and BMP4/7 heterodimers are the main signaling ligands during early mouse development was the first demonstration of a vital functional role for BMP heterodimers in mammals. We are studying how point mutations found within the prodomains of BMP4 and BMP6 in humans disrupt the function of homodimers or heterodimers to cause birth defects and iron overload. 
2. Analysis of a novel signal transduction cascade that coordinately regulates Bmp and TGFß signaling. A distinct focus in the lab is analysis of the novel transmembrane protein, Tril.  We have shown that Tril coordinately regulates the nodal and BMP arms of the TGFß signaling cascade during embryogenesis. Tril mutants have defects in hematopoiesis and the anterior central nervous system fails to form. In adults, Tril functions as a co-receptor for Toll-like receptors (Tlrs), which recognize foreign pathogens and mount an immune response. New studies suggest that Tlrs are also activated by endogenous ligands and are required for neurogenesis and structural plasticity in the brain, but nothing is known about the signaling pathways that are initiated by Tlrs to mediate these non-immune effects. Our ongoing studies are discovering new players in the signaling cascade activated by Tril in early embryos.