The molecular cloning and the elucidation of the gene structures of the acid
(aSMase) and a neutral sphingomyelinases (nSMase) facilitated the structural and functional analysis of these enzymes responsible for
the catabolism of sphingomyelin present ubiquitously in the membrane lipid
bilayer of mammalian cells. The protein and enzymic properties of the glycoprotein aSMase and of a non-glycosylated nSMase residing in the
membranes of the endoplasmic reticulum have been analysed in the native as well as in the recombinant shingomyelinases. Important insight was gained from gene targeting experiments in which an aSMase deficient mouse line was generated
which mimics the neurovisceral form of the human Niemann-Pick disease. The
availability of the cloned aSMase and nSMases led to a genetic
approach to the verification of the concept that these enzymes in the 'sphingomelin
cycle' are responsible for the generation of ceramide regarded as a lipophilic
second messenger in the intracellular signal cascades activated by e.g.
TNF-alpha, Fas ligand or cellular stress.
Cellular localization
Cytoplasmic, Plasma membrane
Comment
Ovarian function
Follicle atresia, Germ cell development
Comment
Witty et al 1996 reported that induction of avian granulosa cell
apoptosis is observed after exposure of apoptosis-resistant granulosa cells to
sphingomyelinase treatment and UV irradiation, which are known to stimulate
endogenous ceramide production.
Expression regulated by
Growth Factors/ cytokines, interleukin
Comment
Santana P, et al reported that interleukin-1 beta stimulates sphingomyelin hydrolysis in cultured
granulosa cells and evidence for a regulatory role of ceramide on progesterone and prostaglandin biosynthesis.
In granulosa cells labeled to isotopic steady-state with [3H]serine, addition of
interleukin-1 beta (IL1 beta) or bacterial sphingomyelinase (SMase) induced a
rapid decrease in cellular [3H]Sphingomyelin
content and a prolonged generation of [3H]ceramide, the immediate
lipid-moiety generated in response to sphingomyelin hydrolysis. In FSH-treated
cells, IL1 beta (0.3-30 ng/ml) inhibited progesterone biosynthesis in a
dose-dependent manner, an effect that was also observed in cells exposed to
increasing concentrations of bacterial SMase (0.003-0.3 U/ml) or the membrane-permeable ceramide analogue N-hexanoylsphingosine (C6-cer:0.1-10 microM). Although bacterial
SMase or the ceramide analogue C6-cer alone did not exactly reproduce the effect
of IL1 beta on granulosa cell prostaglandin E2 (PGE2) biosynthesis, both agents
augmented net PGE2 production and messenger RNA levels of the inducible
prostaglandin endoperoxide synthase/cyclooxygenase (PGHS-2) in
cytokine-treated cells. Collectively, whereas these results show that ceramide
triggers a negative-effector pathway that is both necessary and sufficient to
reproduce the inhibitory effect of IL1 beta on FSH-stimulated granulosa cell
steroidogenesis, they also support the notion that sphingomyelin hydrolysis may be
important for cytokine-induced PGHS-2 expression but not sufficient to reproduce
IL1 beta-stimulated PGE2 biosynthesis.
Ovarian localization
Oocyte, Cumulus, Granulosa, Theca, Luteal cells
Comment
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Morita Y, et al 2000 reported that oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy.
They show that
disruption of the gene for acid sphingomyelinase in female mice suppressed the
normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian
hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or
wild-type oocytes treated with sphingosine-1-phosphate resisted developmental
apoptosis and apoptosis induced by anti-cancer therapy, confirming cell
autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult
wild-type female mice, the event that drives premature ovarian failure and
infertility in female cancer patients, was completely prevented by in vivo
therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway
regulates developmental death of oocytes, and sphingosine-1-phosphate provides
a new approach to preserve ovarian function in vivo.
Species: human
Mutation name: None
type: naturally occurring fertility: None Comment: In Niemann-Pick disease (See OMIM link), lipid, mainly sphingomyelin, accumulates in reticuloendothelial and other
cell types throughout the body. The accumulation in ganglion cells of the central nervous system leads
to cell death. Hepatosplenomegaly, retarded physical and mental growth and severe neurologic
disturbances are features. Symptoms usually develop by 6 months and death occurs by 3 years of age.