Research Abstract:
Fibroblast growth factors (FGFs) are essential molecules for mammalian development and physiology. FGF signaling pathways interact with hedgehog, BMP, TGF Beta and Wnt signaling pathways to regulate cell proliferation, migration and differentiation. Mutations in the genes encoding FGFs and FGF receptors (FGFRs) result in embryonic lethality, developmental defects or physiological abnormalities. Additionally, gain of function mutations in FGFRs result in hereditary craniofacial and skeletal dysplasias in humans.
We are studying FGFs, FGF receptors and a variety of other interacting signaling pathways (hedgehog, Wnt, BMP, TGF beta, VEGF) in mouse embryogenesis and in adult mice with a focus on skeletal, cardiac, vascular and pulmonary development and physiology. Using knockout and conditional knockout technology we have constructed FGF and FGF receptor mutants with defects in these organ systems. Mutant mice are being studied as genetic and developmental model systems for mesodermal and epithelial patterning and growth, and as models for human disease.
We have recently discovered that a subfamily of FGFs acts intracellularly in neurons (iFGFs) and are important for neuronal signal transduction. Disruption of the intracellular signaling molecule, FGF14 results in an anatomically normal mouse with severe neurobehavioral phenotypes including ataxia, seizure, paroxysmal dystonia and cognitive impairment. We are investigating the role of FGF14 as a regulator of neuronal excitability and as an intracellular regulator of voltage gated sodium channel function.
We are investigating the function of a novel multi-transmembrane domain protein family, the Otopetrins. Otopetrin1 was initially identified by positional cloning of the tilted mouse, a mutation that results in vestibular system dysfunction. We have shown that this family of proteins can regulate intracellular calcium and may function as a channel, transporter, or a regulator of calcium in exocytotic vesicles that may contribute to structures required for extracellular biomineralization.
Selected Publications:
White AC, Lavine KJ, Ornitz DM. FGF9 and SHH regulate mesenchymal vegfa expression and development of the pulmonary capillary network. Development 2007 (In Press).
Hughes I, Saito M, Schlesinger PH, Ornitz DM. Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium. Proc Natl Acad Sci USA 2007 104:12023-12028.
Hung IH, Yu K, Lavine KJ, Ornitz DM. FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 2007 307:300-313.
Xiao M, Xu L, Laezza F, Yamada K, Feng S, Ornitz DM. Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol Cell Neurosci 2007 34:366-377.
Lavine KJ, White AC, Park C, Smith CS, Choi K, Long F, Hui CC, and Ornitz DM. Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development. Genes Dev 2006 20:1651-1666.
Last Updated: 10/01/2007 |