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Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion.

ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. TSC has high frequency of osseous manifestations such as sclerotic lesions in the craniofacial region. However, an animal model that replicates TSC craniofacial bone lesions has not yet been described. The roles of Tsc1 and the sequelae of Tsc1 dysfunction in bone are unknown. In this study, we generated a mouse model of TSC with a deletion of Tsc1 in neural crest-derived (NCD) cells that recapitulated the sclerotic craniofacial bone lesions in TSC. Analysis of this mouse model demonstrated that TSC1 deletion led to enhanced mTORC1 signaling in NCD bones and the increase in bone formation is responsible for the aberrantly increased bone mass. Lineage mapping revealed that TSC1 deficient NCD cells overpopulated the NCD bones. Mechanistically, hyperproliferation of osteoprogenitors at an early postnatal stage accounts for the increased osteoblast pool. Intriguingly, early postnatal treatment with rapamycin, an mTORC1 inhibitor, can completely rescue the aberrant bone mass, but late treatment cannot. Our data suggest that enhanced mTOR signaling in NCD cells can increase bone mass through enlargement of the osteoprogenitor pool, which likely explains the sclerotic bone lesion observed in TSC patients.

PROVIDER: S-EPMC4478231 | BioStudies |

REPOSITORIES: biostudies

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