The focus of my lab is to determine the mechanisms of signaling by Fibroblast Growth Factor Receptors (FGFRs) during development and disease conditions.
Extensive Research Description
The focus of my lab is to determine the mechanisms of signaling by Fibroblast Growth Factor Receptors (FGFRs) during development and disease conditions. We are currently pursuing three projects in our laboratory:
Project 1 involves the mechanism of FGFR signaling in craniofacial development. The mammalian skull is composed of 22 separate bones which grow at specialized joints called 'sutures' to accommodate the rapidly growing brain during early development. FGFR mutations cause the premature fusion of cranial sutures prior to the completion of brain growth, a condition called craniosynostosis. We have made several animal models by 'knock-in' gene targeting to explore the mechanism of craniosynostosis caused by FGFR-2 mutations that includes the first animal model for Crouzon-type craniosynostosis syndrome. We are exploring the FGF-responsive transcription factors and signaling molecules that are activated in cranial osteoblast cells using genomic and proteomic approaches.
Project 2 involves the mechanism of FGFR signaling in branching morphogenesis. FGFRs are expressed as two major isoforms, 'b' and 'c'. The b isoforms are expressed in epithelial cell layers, whereas the c isoforms are expressed in the mesenchymal tissues. While the c isoforms play a major role in bone development, the b isoforms play a critical role in the branching morphogenesis of organs. We are using salivary gland development as a model to explore the mechanism of FGFR signaling in branching morphogenesis. We are employing 3-D organ culture, as well as biochemical, cell biological and genomic approaches, to understand the process of branching morphogenesis.
Project 3 involves the mechanism of Klotho-FGFR signaling in calcium and phosphate homeostasis. FGF23 is the largest member of the FGF family and is produced by osteoblasts in bone, released into the circulation like an endocrine hormone and is able to regulate phosphate and calcium re-absorption in the kidney. FGF23 requires Klotho to signal via FGFRs to mediate its endocrine function. Klotho is a single pass type I membrane protein highly expressed in the distal convoluted tubules of kidney and interacts with FGFRs. However, which of the FGFR isoforms that Klotho interacts to regulate phosphate/calcium homeostasis is not known. Therefore, we are creating a genetic tool to identify FGFRs in the distal convoluted tubules of kidney that interact with Klotho and to explore the signaling mechanisms that are involved in calcium and phosphate homeostasis.
- Eswarakumar VP and Schlessinger J. Skeletal overgrowth is mediated by deficiency in a specific isoform of fibroblast growth factor receptor-3. Proc Natl Acad Sci U S A. 104(10):3937-42 (2007)
- Fox MA, Sanes JR, Borza D, Eswarakumar VP, Fassler R, Hudson B, John SW, Ninomiya Y, Pedchenko V, Rheault M, Sado Y, Segal Y, Werle MJ and Umemori H. Distinct target-derived signals organize formation, maturation and maintenance of motor nerve terminals.
- Eswarakumar VP, Özcan F, Lew ED, Bae JH, Tomé F, Booth CJ, Adams DJ, Lax I, and Schlessinger J. Attenuation of signaling pathways stimulated by pathologically activated FGFR2 mutants prevents craniosynostosis. Proc Natl Acad Sci U S A. 103 (49), 18063-8
- Rohmann E, Brunner H, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Emerouglu M, Leroy J, Li Y, Becker C, Lehnerdt K, Cremers CWRJ, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, Bockhoven HV, and Wollnik B. Mutati
- Eswarakumar VP, Lax I and Schlessinger J. Cellular Signaling by FGF receptors. Cytokine Growth Factor Rev. 16(2):139-49 (2005)
- Eswarakumar VP, Horowitz MC, Locklin R, Morriss-Kay GM and Lonai P. A gain of function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proc Natl Acad Sci U S A. 101(34):12555-60 (2004)
- Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM, Lonai P. The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development. 129(16): 3783-93 (2002)