Title

FGF signaling and mandibular morphogenesis

Date of Completion

January 2006

Keywords

Biology, Molecular|Biology, Cell

Degree

Ph.D.

Abstract

Morphogenesis of the mandibular process including the outgrowth of the mandibular processes, the formation of Meckel's cartilage (MC) and the six mandibular bones is regulated by a complex signaling network, including the fibroblast growth factor (FGF) signaling family. A number of FGFs and FGF receptors (FGFRs) are expressed in temporally and spatially regulated patterns in the developing mandible. The unique patterns of expression for Fgfr2 and Fgfr3 suggest their important roles in various aspects of mandibular morphogenesis. In the present study we examined the functions of FGFR2 and FGFR3 in mandibular morphogenesis using retroviral constructs expressing dominant negative forms of these receptors (RCAS-dnFGFR2 and RCAS-dnFGFR3). ^ We demonstrate that inhibition of FGFR3 signaling leads to significant defects in the outgrowth of the mandibular processes, development of MC and the formation of the six mandibular bones in a stage-specific manner. The defects in the outgrowth of the mandibular process induced by dnFGFR3 are not related to disturbances in signaling cascades regulating early mandibular patterning, but related to defects in the morphogenesis of MC and associated mandibular bones. In the developing MC, inhibition of FGFR3 signaling led to a reduction in the size of the initial condensation and reduced cell survival, proliferation and differentiation of the newly formed chondroblasts. In the developing bones, inhibition of FGFR3 signaling led to an absence of early osteogenic condensations, reduced osteoprogenitor/osteoblast proliferation, and reduced survival and differentiation of osteoblasts. ^ Our in situ hybridization and RT-PCR data shows distinct and non-overlapping expression patterns of Fgfr2b and Fgfr2c and their respective ligands (Fgf10 and Fgf9) in the developing mandible, suggesting that reciprocal paracrine signaling loops between different FGFs and different isoforms of FGFR2 regulate chick mandibular morphogenesis. However, inhibition of FGFR2 signaling did not affect the outgrowth of the mandibular process and MC, but led to only mild reductions in the size of four mandibular bones. ^ Our data show novel roles for FGFR3 during chick mandibular skeletogenesis and demonstrate that during early stages of embryogenesis, FGFR3 signaling plays a positive role the proliferation and differentiation of chondrogenic and osteogenic cells.^