Professor of Neurobiology & Anatomy and
Professor of Internal Medicine
Cancer Center Programs: Cell Response & Regulation
B.S. Southern Oregon University
Ph.D. University of Washington
Jan Christian's Lab Page
Jan Christian's PubMed Literature Search
Jan Christian's HCI Profile
Molecular Biology Program
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), Bone morphogenetic (BMP) and Wnt families function in development and disease. Our studies are highly relevant to cancer since BMPs provide context dependent anti-metastatic or oncogenic signals in the tumor environment while aberrant activation of TGFß or Wnt pathways enhance cancer cell growth and metastasis. We use Xenopus as a simple vertebrate model system with which to dissect molecular components of signaling pathways and complement these studies using targeted mutagenesis in mice. Our research program has two major foci:
1) Understanding how BMP activity is regulated by cleavage of the precursor protein
and by interactions with the extracellular matrix.
One current project in the lab investigates genetic interactions between the extracellular matrix molecules, Fibrillins, and BMP4. Mutations in Fbns have been identified in many human cancers, and are believed to promote tumorigenesis through loss of TGFß latency. Our studies show that Fibrillins also positive regulate BMP4 activity through interactions with the prodomain. We are working to understand the molecular mechanisms by which BMP4 and Fibrillins cross regulate each other’s function.
A second project involves analysis of mice carrying a point mutation that prevents proteolytic activation of BMP7. UnlikeBmp7 null mutants, which die after birth, this cleavage mutant mouse dies early in development due to defects in multiple organs. Our findings provide the first genetic evidence that BMP7 functions predominantly as a highly active heterodimer together with BMP2 and BMP4 in mammals, which must be taken into consideration in understanding the impact of mutations in different BMP family members associated with colon and other cancers in humans.
2) Analysis of a novel signal transduction cascade that coordinately regulates TGFß, BMP, and Wnt signaling
A distinct focus in the lab is analysis of signaling downstream of the transmembrane protein, Tril. Tril is upregulated in some endometrial and ovarian cancers, and provides an unfavorable prognostic marker. In adults, Tril functions as a co-receptor for Toll-like receptors, which recognize foreign pathogens and activate NFkB to mount an immune response. We have shown that Tril also activates an NFkB independent pathway that is required to positively regulate Bmp, and negatively regulate Tgfß and Wnt signaling. Our ongoing studies are discovering new players in the signaling cascade activated downstream of Tril, which will be important for understanding whether these non-immune functions contribute to cancer.
- 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.