- Assistant Professor
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- Allen Lab: 734 615 5673 3678 BSRB
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EducationPostdoctoral Fellowship Harvard University Ph.D. University of Wisconsin-Madison B.S. Cornell University
Cell surface regulation of Hedgehog signaling during mouse embryogenesis.
During embryogenesis many developmental decisions are regulated by a relatively small number of secreted growth factors and morphogens. These secreted ligands elicit a multitude of cellular responses, often functioning as morphogens, mitogens, survival factors and chemoattractants within the same tissue. Our research is focused on understanding how these signaling pathways elicit such a diverse set of responses within the developing embryo and how their selective modulation might contribute to the treatment of both developmental diseases and cancer. Specifically, we seek to understand the regulation of Hedgehog (Hh) signaling in development and disease through the study of this pathway during mouse embryogenesis.
Hh signaling proteins govern multiple developmental processes ranging from the establishment of left-right asymmetry to neural patterning and digit specification. Hh ligands also regulate a number of adult homeostatic processes including the maintenance of neural stem cell niches. In humans, impaired Hh signaling leads to severe birth defects, such as holoprosencephaly, while improper Hh pathway activation is associated with a number of cancers, including medulloblastoma, basal cell carcinoma and rhabdomyosarcoma. A defining feature of Hh signaling is that relatively small changes in the concentration of Hh ligand elicit dramatically different cellular responses. This is most evident in the developing neural tube, where Sonic Hedgehog (Shh) signaling is required for the specification of all ventral cell fates. During neural patterning, as little as a two-fold change in Shh ligand concentration is sufficient to specify distinct cell types. This raises the question: How do cells sense subtle differences in ligand concentration? Recent work suggests that feedback mechanisms acting at the level of ligand binding play a critical role in determining the proper cellular response. We study the function of several Hh-binding proteins (Ptch1, Ptch2, and Hhip1) that antagonize Hh function, as well as the characterization of three novel Hh-binding cell surface proteins, Gas1, Cdo and Boc that promote Hh signaling. We are also pursuing the identification and characterization of additional cell surface proteins that may regulate Hh signaling during embryogenesis. We seek to explore the functions of these molecules using a wide range of approaches, including mouse developmental genetics, biochemistry, and cell biology.
Keywords: Hedgehog, mouse, neural patterning, embryogenesis, signaling, development, digit specification, craniofacial development
- Chamberlain, C.E., Jeong, J., Guo, C., Allen, B.L., and McMahon, A.P., Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning, Development, 2008, Mar; 135 (6): 1097-1106. Epub 2008 Feb 13.� PMID: 18272593.
- Allen, B.L., Tenzen, T., and McMahon, A.P., The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development, Genes Dev., 2007, May 15; 21 (10): 1244-1257. PMID: 17504941.
See comment in: Sci STKE. 2007 Sep 11; 2007 (403): pe50. PMID: 17848687.
- Tenzen, T., Allen, B.L., Cole, F., Kang, J.S., Krauss, R.S., and McMahon, A.P., The cell surface
membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback networks in mice, Dev. Cell, 2006, May; 10 (5): 647-656. Epub 2006 Apr 27. PMID: 16647304
See comment in: Cell. 2006 May 5; 125 (3): 435-438. PMID: 16678090.
- Jasuja, R.*, Allen, B.L.*, Pappano, W.N.*, Rapraeger, A.C., and Greenspan, D.S., Cell-surface heparan sulfate proteoglycans potentiate chordin antagonism of bone morphogenetic protein signaling and are necessary for cellular uptake of chordin, J.Biol. Chem., 2004, Dec 3; 279 (49): 51289-51297. Epub 2004 Sep 20. PMID: 15381701
- Griffith, B.R., Allen, B.L., Rapraeger, A.C., and Kiessling, L.L., A Polymer Scaffold for Protein Oligomerization, J. Am. Chem. Soc., 2004, Feb 18; 126 (6): 1608-1609. PMID: 14871072
- Allen, B.L., and Rapraeger, A.C., Spatial and temporal expression of heparan sulfate in mouse development regulates FGF and FGF receptor assembly, J. Cell. Biol., 2003, Nov 10; 163 (3): 637-648. PMID: 14610064
- Motamed, K., Blake, D.J., Angello, J.G., Allen, B.L., Rapraeger, A.C., Hauschka, S.D., and Sage, E.H, Fibroblast Growth Factor Receptor-1 Mediates the Inhibition of Endothelial Cell Proliferation and the Promotion of Skeletal Myoblast Differentiation by SPARC: A Role for Protein Kinase A, J. Cell. Biochem., 2003 Oct 1; 90(2): 408-423. PMID: 14505356
- Allen, B.L., Filla, M.S., and Rapraeger, A.C., Role of heparan sulfate as a tissue-specific regulator of FGF-4 and FGF receptor recognition, J.Cell. Biol. 2001 Nov 26; 155(5): 845-857. PMID: 11724824
- Wang, Y.*, McMahon, A.P., and Allen, B.L.*, Shifting paradigms in Hedgehog signaling, Curr. Opin. Cell Biol., 2007, Apr; 19(2): 159-165. Epub 2007 Feb 15. PMID: 17303409
*authors contributed equally to this work