Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development

Abstract

Sphingosine phosphate lyase 1 (SGPL1) is a highly conserved enzyme that irreversibly degrades sphingosine-1-phosphate (S1P). Sgpl1-knockout mice fail to develop germ cells, resulting in infertility. However, the molecular mechanism remains unclear. The results of the present study showed that SGPL1 was expressed mainly in granulosa cells, Leydig cells, spermatocytes, and round spermatids. Sgpl1 deletion led to S1P accumulation in the gonads. In the ovary, S1P decreased natriuretic peptide receptor 2 (NPR2) activity in granulosa cells and inhibited early follicle growth. In the testis, S1P increased the levels of cyclin-dependent kinase inhibitor 1A (p21) and apoptosis in Leydig cells, thus resulting in spermatogenesis arrest. These results indicate that Sgpl1 deletion increases intracellular S1P levels, resulting in the arrest of female and male germ cell development via different signaling pathways.

A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

“…Sgpl1 −/− mice have suboptimal corticosterone production ( 29 ) and their adrenals show disrupted adrenocortical zonation, reduced expression of steroidogenic enzymes and loss of the typical sub-capsular clusters of aldosterone synthase ( 4 ). Deletion of Sgpl1 abrogates germ cell development in gonads rendering both male and female Sgpl1 −/− mice sterile and attributed to intra-gonadal accumulation of S1P ( 30 , 31 ). Testes exhibit reduced spermatids and Leydig cell numbers, while increased pre-antral follicle atresia is noted in murine ovaries ( 30 , 31 ).…”

“…Deletion of Sgpl1 abrogates germ cell development in gonads rendering both male and female Sgpl1 −/− mice sterile and attributed to intra-gonadal accumulation of S1P ( 30 , 31 ). Testes exhibit reduced spermatids and Leydig cell numbers, while increased pre-antral follicle atresia is noted in murine ovaries ( 30 , 31 ).…”

“…Ceramide does potentially reduce the transactivation capability of thyroid transcription factor 1 ( TTF-1 / NKX2-1 ) in vitro ( 39 ), which regulates the expression of genes essential for thyroid hormone biosynthesis ( 40 , 41 , 42 , 43 ). While SGPL1 deficiency in humans does not consistently translate to growth failure, postnatal growth retardation is a feature seen in Sgpl1 −/− mice ( 30 ). Ongoing evaluation of auxology in all patients is required to assess any impact of SGPL1 deficiency on growth and it is possible that comorbidities including renal disease and endocrinopathy ultimately affect growth, particularly if identified late or not adequately treated.…”

SphK-produced S1P in somatic cells is indispensable for LH-EGFR signaling-induced mouse oocyte maturation

“…Ovaries COCs were isolated from eCG-primed mice or mice at 2 h post-hCG. In some experiments, COCs from eCG-primed mice were collected after different drug treatments for 2 h. More than 1 mg/mL ovarian protein samples or 1500 COC samples per group were used for analyzing S1P levels according to previous reports 19,38 . Brie y, 12.5 µL of sample suspension, 5 µL of internal standards (1 ng/mL for C17-S1P) and 32.5 µL of methanol were added to a 1.5 mL tube.…”

“…17 ). S1P can mobilize endoplasmic reticulum (ER) calcium storage to elevate calcium levels 18 , which is of crucial importance in regulating cell function, including the reduced NPR2 activity in cumulus cells for oocyte meiotic resumption 9,10,19 . S1P actions are also mediated by binding to a family of ve high-a nity G-protein-coupled receptors, designated S1PR1-5 (ref.…”