Sinking our teeth into Costello syndrome: Ras signaling regulates enamel deposition in humans and mice.

Goodwin A1, Oberoi S1, Charles C1, Groth JC1, Fairley CF1, Chen X2, Fagin JA2,3, Rauen KA4,5, and Klein OD1,4

1Department of Orofacial Sciences, UCSF, San Francisco, CA 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center NY, NY 3 Department of Medicine, Memorial Sloan Kettering Cancer Center NY, NY 4Department of Pediatrics, Division of Medical Genetics, UCSF, San Francisco, CA 5 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

Ras/MAPK signaling is critical in animal development, and receptor-tyrosine kinase signaling, which activates Ras signaling, is known to play an important role in tooth development. Our previous work has shown that increasing Ras/MAPK signaling by inactivating Sprouty genes adversely affects tooth morphogenesis. Here, we directly examined the effects of activating Ras/MAPK signaling in both humans and mice. Costello Syndrome (CS) is caused by a heterozygous de novo germline mutation in HRAS that results in a constitutively active Ras protein. We examined a cohort of CS patients at the 2009 Costello Syndrome International Conference and identified a number of craniofacial and dental anomalies. The most striking finding was that a large majority of patients presented with a pronounced enamel defect. Micro computed tomography of exfoliated primary teeth from CS patients showed a significant decrease in enamel thickness compared to controls. We next examined the CS mouse model and found that the mice also had an enamel defect. Further inspection revealed disorganization of the ameloblasts in the mouse incisor. We are currently studying cell proliferation and polarity of the amelobasts in the mutant mice incisors and using an ameloblast-like cell line. Together, our studies point to a role for Ras signaling in regulation of cell polarity and deposition of mineralized matrices.

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