The fibroblast growth factors (FGFs) consist of a large family of ligands that bind to membrane-spanning tyrosine kinase receptors (FGFRs). Activation of the receptors by ligand binding leads to the activation of a variety of signal transduction pathways that include the MAP kinases as well as the AKT survival pathway. The FGFs are involved in many cellular processes such as mitogenesis, differentiation, migration and wound healing. Although FGF receptors are expressed in many different cell types, aberrant FGF oversignaling in vivo particularly affects bone cells ?chondrocytes and osteoblasts (see review 2005). Genetic studies from humans and mice have indicated that FGFs play a crucial role in bone development. Broadly, our long-term goal is to understand the physiology of FGF function at a molecular genetic level and to study the mechanism by which FGFs cause proliferation cellular transformation or differentiation. We have used mutant FGF receptors (dominant-negative or constitutively activated) that can either block FGF-signaling, or activate it in an uncontrolled manner to study FGF signaling in various cell types. Our current focus is to understand how FGFs affect osteoblasts, the bone-forming cells, during skull development. The development of the skull is a highly coordinated process involving a complex interplay of signaling systems. The flat bones of the skull, the calvaria, are formed through the maturation of a layer of mesenchymal cells, which condense directly to bone-forming osteoblasts Perturbations in the regulatory signals during this process can lead to craniosynostosis, or premature suture closure, which is associated with several human, autosomal dominant craniofacial disorders. Craniosynostosis syndromes such as Crouzon, Apert, and Jackson-Weiss, are due to activating mutations in the fibroblast growth factor receptors, particularly in FGFR2, We have shown that FGF signaling has distinct effects on early and late-stage osteoblasts. In immature cells, FGF signaling induces proliferation and inhibits differentiation, but in mature osteoblasts, it leads to an increased rate of apoptosis. The FGFs have not previously been implicated in programmed cell death and are usually considered as anti apoptotic factors. FGF-induced apoptosis in mature osteoblasts may therefore be indicative of a novel signaling mechanism in these cells. By studying signal transduction and gene expression changes in osteoblasts with mutant FGFRs, we aim to uncover the molecular mechanisms that underlie the FGF-related bone pathologies. Our goals are to determine how FGFs elicit maturation stage-specific responses in osteoblasts, and how this affects calvarial bone formation in development. These questions are being addressed both in cell culture studies and in animal models in which FGF signaling is genetically altered. Our recent work involved analysis of the gene expression profiles of osteoblasts expressing FGFR2 activating mutations found in Crouzon and Apert syndromes (C342Y or S252W). We found a striking down-regulation of the expression of many Wnt target genes and a concomitant induction of the transcription factor Sox2. Most of these changes could be reproduced by treatment of osteoblasts with exogenous FGF. Wnt signals promote osteoblast function and regulate bone mass. Sox2 is expressed in calvarial osteoblasts in vivo and we showed that constitutive expression of Sox2 inhibits osteoblast differentiation and causes down-regulation of the expression of numerous Wnt target genes. Sox2 also associates with beta-catenin in osteoblasts and can inhibit the activity of a Wnt responsive reporter plasmid through its COOH-terminal domain. Our results indicated that FGF signaling could control many aspects of osteoblast differentiation through induction of Sox2 and regulation of the Wnt-beta-catenin pathway. We are also extending these studies in a mouse model of Apert syndrome and in a bone specific knockout of Sox2.