Inducible transient expression of Smpd3 prevents early lethality in fro/fro mice

Abstract

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.

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…In vivo, sphingolipid metabolism plays a critical role in skeletogenesis; mouse models lacking the ceramide-generating neutral sphingomyelinase 2 enzyme (nSMase2/SMPD3 -gene-targeted Smpd3 K/K and fro/fro mice) display gross skeletal abnormalities, including deformed long bones, short-limb dwarfism, hypomineralisation, delayed dentin mineralisation and enamel formation (Aubin et al 2005, Stoffel et al 2005, Alebrahim et al 2014. Conversely, the overexpression of SMPD3 in osteoblasts only (fro/fro;Col1a1-Smpd3 mice) corrects embryonic bone abnormalities, demonstrating a direct role of SMPD3 in skeletal mineralisation (Khavandgar et al 2011(Khavandgar et al , 2013.…”

Role of Neutral Sphingomyelinase-2 (NSM 2) in the Control of T Cell Plasma Membrane Lipid Composition and Cholesterol Homeostasis

“…NSM2-deficient mice show high embryonic lethality, dwarfism and fragile bones. This prevented studies on NSM2 function in the immune system (Stoffel et al, 2005; Alebrahim et al, 2014). Furthermore, the lack of specific and sensitive antibodies for detection of the rather sparse amounts of NSM2 expressed in T cells hampered the progress in the field.…”

Pten regulates endocytic trafficking of cell adhesion and signaling molecules to pattern the retina

“…Strikingly, using RNAscope in situ hybridization, Smpd3 transcripts were largely restricted to the inner INL and the GCL, closely matching the pattern of Pax6 transcript distribution, an amacrine cell marker, and overlapping with Pten , which was expressed throughout the INL (Figure 6E). To test the functional significance upon amacrine cell spacing in the absence of nSmase2, we acquired fro/fro mice, which harbor a spontaneous mutation in Smpd3 , the gene encoding for this enzyme (Alebrahim et al, 2014). Interestingly, both ChAT + and TH + amacrine cell mosaics were normal in adult Smpd3 null mutant mice (Figure S4A,B).…”

“…RRID:IMSR_JAX:024578. Common Name: P0-3.9GFPCre), fro/fro (Alebrahim et al, 2014), Dscam del17 (Fuerst et al, 2008) B6.CBy- Dscam del17 /RwbJ. Strain #:008000.…”