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Generation of Viable Fro/fro Mice and Analyses of Their Mineralized Tissue

Generation of Viable Fro/fro Mice and Analyses of Their Mineralized Tissue

2014 . Sharifa Alebrahim



Generation of Viable Fro/fro Mice and Analyses of Their Mineralized Tissue
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About the book

"Sphingomyelin phosphodiesterase 3 (SMPD3), a plasma membrane-bound enzyme, cleaves sphingomyelin to generate ceramide and phosphorylcholine. These two bioactive lipid metabolites regulate many cellular activities. A recessive mutation called fragilitas ossium (fro) in the Smpd3 gene leads to impaired bone and tooth mineralization in the fro/fro mice. Most fro/fro mice do not survive beyond the perinatal period that makes it difficult to get enough number of mice for the phenotypic analyses. Our specific aims are: 1) Generate viable fro/fro mice on a C57BL/6-C3H/HeN mixed background to analyze their tooth mineralization defects; and 2) Generate viable fro/fro mice on a pure C57BL/6 background by transient expression of Smpd3 during late embryonic development, and characterize their skeletal phenotype. We observed an improved survival of the fro/fro mutants on the C57BL/6-C3H/HeN mixed background. Examination of the teeth of these mixed background-mutants revealed a delayed mantle dentin mineralization and consequently, a delay in enamel mineralization. These tooth abnormalities progressively improved with time. The restoration of Smpd3 expression driven by a Col1a1-Smpd3 transgene in the odontoblasts corrected the tooth mineralization defects in fro/fro;Col1a1-Smpd3 mice. In order to obtain viable fro/fro mice on the C57BL/6 background, we followed a strategy based on the Tet-On inducible gene expression system. Following a complex breeding strategy, we generated fro/fro;ROSA-rtTA;TRE-Smpd3 compound mutant mice. The ubiquitous ROSA promoter drives the expression of rtTA transactivator in these mice. When treated with doxycycline, TRE-Smpd3 expression was induced in the cells synthesizing the rtTA protein in the compound mutants. The doxycycline treatment given to the pregnant mothers during the late gestation period resulted in the correction of the limb deformities and the skeletal mineralization defects in fro/fro;ROSA-rtTA;TRE-Smpd3 embryos. However, induction of Smpd3 expression in the adolescent fro/fro;ROSA-rtTA;TRE-Smpd3 mice was not sufficient to correct the defects in trabecular bone mineralization and the impaired growth of the long bones. This novel mouse model will be a useful tool to study SMPD3 biology in vivo."--






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