Research
Overview
The two arms of the Transforming Growth Factor Beta (Tgf-ß) superfamily are activated by Tgf-ß/nodal and Bone morphogenetic protein (Bmp) ligands. Downstream of receptor activation, pathway specific Smad proteins are phosphorylated and migrate to the nucleus to regulate expression of target genes. The two pathways often operate simultaneously to achieve differing goals. During development, for example, nodal signaling establishes anterior fate, while Bmps specify ventral and posterior fate. In cancer stem cells, Bmps inhibit self-renewal, and thus act as a barrier to tumor progression, whereas nodal promotes self-renewal to enhance cancer stem cell proliferation. A proper balance of Bmp and nodal signaling is critical for normal development and to prevent birth defects and disease. The goal of our research program is to understand how nodal and BMP signaling is coordinately regulated during embryonic development. In addition, we study how mutations in BMP genes cause birth defects and disease in humans. We use the frog as a simple model system to dissect molecular components of signaling pathways, and complement these with studies in mice carrying knock in mutations.
Current Projects
Analysis of a novel signal transduction cascade that coordinately regulates Bmp and Nodal signaling
We identified Tlr4 interactor with leucine-rich repeats (tril) as a gene induced downstream of BMP signaling. Tril enhances BMP signaling by promoting degradation of the BMP inhibitor, Smad7, and simultaneously dampens nodal signaling by activating the nodal inhibitor, Nedd4l. In adults, Tril functions as a co-receptor for Toll-like receptors (Tlrs), which recognize foreign pathogens and mount an immune response. Vertebrate Tlrs can also be activated by endogenous ligands but nothing is known about the downstream signaling pathways that mediate these non-immune effects. Our ongoing studies are discovering novel players in a non-canonical Tlr-like signaling cascade that is activated by Tril in early embryos to concurrently inhibit nodal signaling and boost BMP signaling.
Understanding how point mutations in the prodomain of BMP precursor proteins cause birth defects and disease 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. In humans, heterozygous point mutations within the prodomain of BMP6 or BMP4 are associated with iron overload disease, or with a spectrum of eye, brain, palate and kidney defects, respectively. We are studying whether and how these prodomain point mutations disrupt the function of homodimers or heterodimers to cause birth defects and disease.