Abstract
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis. They did develop a prominent skin phenotype with marked thickening of the dermis with accumulation of mast cells, that was minimally responsive to systemic rapamycin therapy, and was quite different from the pathology seen in human TSC skin lesions. Recombination and loss of Tsc1 was demonstrated in skin fibroblasts in vivo and in cultured skin fibroblasts. Loss of Tsc1 in fibroblasts in mice does not lead to a model of angiomyolipoma or lymphangioleiomyomatosis.
Highlights
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder due to inactivating mutations in either TSC1 or TSC2
Through initial breeding experiments we found that Tsc1ccFsp-cre+ mice were generated at Mendelian ratios, displayed no unusual mortality through the age of 6 months, and that both sexes were fertile
Tsc1ccFsp-cre+ mice began to die at 6 months and had a median survival of 338 days in contrast to Tsc1cwFsp-cre+ and Tsc1cc littermates (Fig 1A, p < 0.0001)
Summary
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder due to inactivating mutations in either TSC1 or TSC2. There are well-established consensus diagnostic criteria for TSC; the major clinical criteria include angiofibromas or fibrous cephalic plaque, ungual fibromas, shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis [1]. Similar findings have been made in the majority of sporadic angiomyolipoma and lymphangioleiomyomatosis lesions [3,4,5, 8]. Heretofore no mouse model has been generated which replicates the core features of any of these TSC tumors, including angiofibromas, ungual fibromas, shagreen patch, angiomyolipomas, or lymphangioleiomyomatosis. We sought to generate such a model by targeting biallelic deletion of Tsc to fibroblasts. Fibroblasts or a closely related cell type are thought to be PLOS ONE | DOI:10.1371/journal.pone.0167384. Fibroblasts or a closely related cell type are thought to be PLOS ONE | DOI:10.1371/journal.pone.0167384 December 1, 2016
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