BA – Williams College, Williamstown, Massachusetts
PhD – University of Washington, Seattle
Postdoctoral Fellowship – University of Washington, Seattle
Postdoctoral Fellowship – University of California at San Diego, La Jolla
- The embryonic specification of hematopoietic stem cells
- The integrated development of the vascular and hematopoietic systems
- The molecular basis of leukemia
Cancer and embryonic development are closely related. The Clements laboratory uses zebrafish to investigate two major questions: What are the molecular and cellular components of the developmental specification niche for hematopoietic stem cells (HSCs)? How are normal signaling pathways co-opted during malignant transformation to induce cellular proliferation and migration—desirable processes when building an organism that can cause disease when activated in adult life?
We have recently shown that non-canonical Wnt signaling is critical for specification of HSCs during vertebrate development (Clements et al., Nature 2011). Wnt16 signaling appears to direct early formation of a vascular smooth muscle cell (VSMC) niche that induces HSC fate commitment from endothelial precursors in the primitive dorsal aorta. Strikingly, many of the Wnt signaling factors involved in this process are also aberrantly expressed in B cell leukemias. In the short term, we will define the downstream molecular factors and morphogenetic events governed by Wnt16 signaling that are responsible for specifying HSCs during development. In addition, we will determine how inappropriate activity of this pathway contributes to leukemia.
Our studies will inform long-term efforts to produce HSCs in vitro for regenerative medicine and transplantation therapies, while establishing a paradigm for using zebrafish to investigate whether and how candidate oncogenes contribute to transformation and cooperatively direct specific clinical progressions. Ultimately we seek to develop zebrafish disease models as a platform for cancer therapeutic studies and high throughput drug discovery.
Damm EW, Clements WK. Pdgf signalling guides neural crest contribution to the haematopoietic stem cell specification niche. Nature Cell Biology 19:457-467, 2017.
Genthe JR, Clements WK. R-spondin-1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways. Development 144:590-600, 2017.
Butko E, Distel M, Pouget C, Weijts B, Kobayashi I, Ng K, Mosimann C, Poulain FE, McPherson A, Ni C-W, Stachura DL, Del Cid N, Lawson ND, Dorsky R, Clements WK, Traver D. Gata2b is an early marker of hemogenic endothelium and is required for hematopoietic stem cell emergence. Development 142:1050-61, 2015.
Lee Y, Manegold JE, Kim AD, Pouget C, Stachura DL, Clements WK, Traver D. FGF signaling specifies hematopoietic stem cells through its regulation of somitic Notch signaling. Nat Commun 5:5583, 2014. 10:doi:10.1038/ncomms6583
Kim AD, Melick C, Clements WK, Stachura DL, Distel M, Traver D. Discrete Notch signaling requirements in the specification of hematopoietic stem cells. EMBO J 33:2363-2373, 2014.
Clements WK, Traver D. Signalling pathways that control vertebrate haematopoietic stem cell specification. Nature Rev Immunol 13:336-348, 2013.
Clements WK, Traver D. Fish Pharming: Zebrafish Anti-Leukemia Screening. Blood 119:5614-5, 2012.
Clements WK, Kim AD, Ong KG, Moore JC, Lawson ND, Traver D. A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. Nature 474:220-224, 2011.
Clements WK, Ong KG, Traver D. Zebrafish wnt3 is expressed in developing neural tissue. Dev Dyn 238:1788-95, 2009.
Clements WK, Kimelman D. “Analysis of Wnt Signaling in Xenopus Embryos” in Analysis of Growth Factor Signaling in Embryos. Whitman, M. and Sater, A.K., eds. Taylor & Francis Group, LLC, Boca Raton, FL:1-27, 2006.
Clements WK, Kimelman D. LZIC regulates neuronal survival during zebrafish development. Dev Biol 283:322-334, 2005.
Xing Y, Clements WK, Trong IL, Hinds TR, Stenkamp R, Kimelman D, Xu W. Crystal structure of a Beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Mol Cell 15:523-533, 2004.
Xing Y, Clements WK, Kimelman D, Xu W. Crystal structure of a Beta-catenin/Axin complex suggests a mechanism for the Beta-catenin destruction complex. Genes & Dev 17:2753-2764, 2003.
Clements WK, Kimelman D. Wnt Signaling Gets Xeeky. Nat Cell Biol 5:861-863, 2003.
Graham TA, Clements WK, Kimelman D, Xu W. The crystal structure of the Beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell 10:563-571, 2002.
Melby AE, Clements WK, Kimelman D. Regulation of dorsal gene expression in Xenopus by the ventralizing homeodomain gene Vox Dev Biol 15:293-305, 1999.
Last update: April 2017