Bone Morphogenetic Proteins, Hematopoiesis, Signal transduction during Embryonic Patterning
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:
- 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.
- 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.
- Christian, J.L. (2021) A tale of two receptors: Bmps recruit two type I receptors but use the kinase activity of only one, PNAS, 118 (19) e2104745118
- Kim, H-S, Green, Y.S., Xie, Y. and Christian, J.L. (2021) Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l, PNAS, in press
- Kim, H.K., Neugebauer, J.M., McKnite, A., Tilak, A., and Christian, J.L. (2019) BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis, eLife 8:e48872. PMCID:PMC6785266
- Kim, H-S., McKnite, A., Xie, Y. and Christian, J.L. (2018) Fibronectin type III and intracellular domains of Toll-like receptor 4 interactor with leucine-rich repeats (Tril) are required for developmental signaling. MBoC, 29:523-531.
- Christian, J.L. and Heldin, C-H. (2017) The TGFß superfamily in Lisbon: navigating through development and disease. Development, 144:4476-4480
- Huang, W-C, Ferris, E., Cheng, T., Hörndli, C., Gleason, K., Tamminga, C., Wagner, J., Boucher, K., Christian, J.L. and Gregg, C. (2017) Diverse Non-Genetic Allele Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain, Neuron, 93(5):1094-1109
- Green, Y.S., Mimoto, M.S., Kwon, S., Xi, Y. and Christian, J.L. (2016) Tril targets Smad7 for degradation to allow hematopoietic specification in Xenopus embryos, Development, 143:4016-4026.
- Mimoto, M.S., Kwon, S., Green, Y.S., Goldman, D., and Christian, J.L. (2015) GATA2 regulates Wnt signaling to promote primitive red blood cell fate. Dev. Biol., 407:1-11.
- Neugebauer J.M., Kwon, S., Kim, H., Donley, N., Tilak, A., Sopory, S., and Christian, J.L. (2015) The prodomain of BMP4 is necessary and sufficient to generate BMP4/7 heterodimers with enhanced in vivo bioactivity. PNAS, 112(18):E2307-2316.
- Tilak, A., Nelsen, S., Kim, H., Donley, N. McKnite, A., Lee, H. andChristian, J. (2014) Simultaneous rather than ordered cleavage of the BMP4 prodomain leads to ligand loss in mice. Development, 141:3062-3071.
- Christian, J.L. (2012) Morphogen gradients in development: from form to function. WIREs Dev Biol, 1:3–15.
- Mimoto, M.S. andChristian, J.L. (2012) Friend of GATA (FOG) Interacts with the Nucleosome Remodeling and Deacetylase Complex(NuRD) to Support Primitive Erythropoiesis in Xenopus laevis. PLoS One, 7(1):e29882.