Nan Hatch, DMD, MS, PhD
Assistant Professor
Department of Orthodontics and Pediatric Dentistry

Overview. Craniosynostosis is a debilitating clinical condition characterized by the premature fusion of cranial sutures.  The prevalence of craniosynostosis is high, at approximately 1 in 2500 live births, and treatment is currently limited to surgery, genetic counseling, orthodontics, medical and social support. Greater understanding of the molecular pathogenesis of craniosynostosis will aid in the development of interceptive or adjunctive biologic treatments for patients with this medically and socially challenging condition.

Craniosynostosis can occur sporadically, or as part of one of several known genetic syndromes. Because the more common forms of syndromic craniosynostosis are associated with mutations in fibroblast growth factor receptors (FGFR’s), we are interested in understanding the role of FGF signaling in bone mineralization and craniofacial development.

FGF2 regulates expression of pyrophosphate generating enzymes.  Previous research indicates that fibroblast growth factors have contradictory short and long term effects upon bone mineralization, and that FGF2 may stimulate expression of factors that prevent mineralization in the short term and enhance it in the long term. Pyrophosphate is an ideal example of such a factor in that pyrophosphate inhibits hydroxyapatite deposition and crystal growth, yet pyrophosphate also serves as a critical source of phosphate to enhance bone mineralization when it is hydrolyzed by the osteoblastic enzyme, alkaline phosphatase. We find that FGF2 dramatically increases expression of the pyrophosphate generating enzyme, PC-1, while inhibiting expression of alkaline phosphatase in calvarial pre-osteoblastic cells. We are currently working towards understanding the developmental function of pre-osteoblastic PC-1, and establishing the relative contribution of pre-osteoblastic PC-1 activity in the overall effects of FGF2 on osteoblast differentiation and bone mineralization.

Biochemical effects of craniosynostosis syndrome associated mutations in fibroblast growth factor receptor-2 (FGFR2). In an effort to better understand the biochemical consequences of craniosynostosis associated mutations on FGF receptor function, we are investigating the effect of the FGFR2^C278F mutation of Crouzon craniosynostosis syndrome on receptor expression, trafficking and signaling. We find that FGFR2^C278F exhibits increased degradation and limited cellular sub-localization in calvarial pre-osteoblastic cells, and that this is likely the result of incomplete receptor glycosylation. Glycosylation deficient FGFR2 and FGFR2^C278F are active in the absence of ligand and restricted to ER and Golgi subcellular compartments. Our results raise new questions concerning the mechanism by which FGFR2 mutations influence craniosynostosis.  Our findings indicate that, depending on cell type, auto-activating mutations in FGFR2 might influence craniofacial development by causing enhanced FGFR2 signaling, by causing FGFR2 signaling from an inappropriate subcellular compartment (ER and Golgi versus cell surface and endosomal membranes), or by enhancing FGFR2 degradation to such an extent that total FGFR2 signaling is diminished.  To determine which of these mechanisms pertains to craniosynostosis, we are currently working towards the development of methods to address the extent and subcellular locus of FGFR2 activation in situ. 

Link to Nan Hatch Biosketch