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Jan Christian

Professor of Neurobiology & Anatomy and
Professor of Internal Medicine

Jan Christian

B.S. Southern Oregon University

Ph.D. University of Washington

Research

References

jan.christian@neuro.utah.edu

Jan Christian's Lab Page

Jan Christian's PubMed Literature Search

Molecular Biology Program

Bone morphogenetic proteins, Hematopoiesis

Signal transduction during embryonic patterning

Research

The Christian lab studies cell-cell signaling in development and disease. Bone morphogenetic proteins (Bmps) and Wnts are critical signaling molecules that regulate stem cell function and cell fate specification, and misregulation of either of pathway causes birth defects, degenerative diseases and cancer.

Bmp4 is generated as an inactive precursor protein that dimerizes and is cleaved to generate the active ligand and a prodomain fragment.  Although the Bmp4 prodomain lacks signaling activity, it is essential for full function since mutations within the prodomain cause human congenital anomalies including cleft palate, eye, kidney and bone defects. We use targeted mutagenesis in mice together with cell biological and biochemical approaches in Xenopus embryos to understand how the prodomain regulates the activity of mature Bmp4.  One current project in the lab investigates genetic interactions between the extracellular matrix molecule, Fibrillin1, and Bmp4. Mutations in fibrillin1 underlie the human genetic disorder, Marfan syndrome, which leads to pulmonary fibrosis and aortic aneurysm. Our results support a model in which interactions between the Bmp4 prodomain and Fibrillin1 are required to generate a fully active Bmp4 ligand, and loss of these interactions contributes to Marfan syndrome pathology.

A distinct focus in the lab is analysis of the novel transmembrane protein, Tril.  We have shown that Tril coordinately regulates Bmp and Wnt signaling during embryogenesis, and is required for specification of blood and formation of the anterior central nervous system. 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.

References

  1. HuangW-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

  2. 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.

  3. 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.
  4. 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.
  5. 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.
  6. Christian, J.L. (2012) Morphogen gradients in development: from form to function. WIREs Dev Biol, 1:3–15.
  7. 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.
  8. Kwon, S. andChristian, J.L. (2011) Sortilin associates with TGF-β family proteins to enhance lysosome-mediated degradation. J Biol Chem, 286:21876.
  9. Sopory, S., Kwon, S., Wehrli, M. andChristian, J.L. (2010) Regulation of Decapentaplegic activity by tissue-specific cleavage of an upstream site within the prodomain. Developmental Biology, 346:102-12.
  10. Nelsen, S.M. andChristian, J.L. (2009) Site-specific cleavage of Bone morphogenetic protein4 (BMP4) by furin, PC6 and PC7. J Biol Chem, 284:27157-66.
  11. Goldman, D.C., Bailey, A.S., Pfaffle, D.L., Masri, A.,Christian, J.L.and Fleming, W.H. (2009) BMP4 Regulates Adult Hematopoietic Stem Cell Maintenance in vivo. Blood, 114:4393-401.
  12. Goldman, D.C., Donley, N. andChristian, J.L. (2009) Genetic interaction betweenBmp2 andBmp4 reveals shared functions during multiple aspects of mouse organogenesis. Mech Dev, 126:117-27.

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Last Updated: 8/3/17