Alebrahim Sharifa, Khavandgar Zohreh, Marulanda Juliana, Murshed Monzur
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
Genesis. 2014 May;52(5):408-16. doi: 10.1002/dvg.22765. Epub 2014 Mar 13.
Sphingomyelin phosphodiesterase 3 (SMPD3) is a pleiotropic lipid metabolizing enzyme involved in multiple physiological processes. A deletion mutation in the murine Smpd3 gene called fragilitas ossium (fro) leads to severe skeletal abnormalities in the developing fro/fro embryos. Although fro/fro mice can be useful to study many different aspects of SMPD3 functions, their perinatal lethality makes it difficult to generate a sufficient number of mice for controlled studies. In fact, on the C57BL/6 genetic background, none of the fro/fro mice survive beyond the perinatal stage. In this study, we used the "Tet-On" inducible gene expression system to express Smpd3 transiently in fro/fro;ROSA-rtTA;TRE-Smpd3 embryos on the C57BL/6 background. This induced Smpd3 expression corrected all the skeletal abnormalities in these embryos and prevented their early death. 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.
鞘磷脂磷酸二酯酶3(SMPD3)是一种多效性脂质代谢酶,参与多种生理过程。小鼠Smpd3基因中的一种缺失突变称为骨脆弱症(fro),会导致发育中的fro/fro胚胎出现严重的骨骼异常。尽管fro/fro小鼠对于研究SMPD3功能的许多不同方面可能有用,但其围产期致死性使得难以产生足够数量的小鼠用于对照研究。事实上,在C57BL/6遗传背景下,没有一只fro/fro小鼠能存活至围产期之后。在本研究中,我们使用“Tet-On”诱导型基因表达系统在C57BL/6背景的fro/fro;ROSA-rtTA;TRE-Smpd3胚胎中瞬时表达Smpd3。这种诱导的Smpd3表达纠正了这些胚胎中的所有骨骼异常并防止了它们的早期死亡。然而,在青春期fro/fro;ROSA-rtTA;TRE-Smpd3小鼠中诱导Smpd3表达不足以纠正小梁骨矿化缺陷和长骨生长受损。这种新型小鼠模型将成为在体内研究SMPD3生物学的有用工具。