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GIV/Girdin, a non-receptor modulator for Gαi/s, regulates spatiotemporal signaling during sperm capacitation and is required for male fertility.

ABSTRACT: For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV (CCDC88A), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men.

SUBMITTER: Reynoso S

PROVIDER: S-EPMC8376251 | biostudies-literature |

REPOSITORIES: biostudies-literature

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GIV/Girdin Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

Project description:For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract, and later undergo acrosomal reaction (AR) upon encountering an egg. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of KO mice and cell-penetrating peptides, here we show that GIV (CCDC88A), a guanine nucleotide-exchange factor (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine sperms. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testes and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and the etiology of infertility in men.

2021-08-16 | GSE171704 | GEO

GIV/Girdin Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

Project description:GIV/Girdin Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

| PRJNA720623 | ENA

A sperm ion channel required for sperm motility and male fertility.

Project description:Calcium and cyclic nucleotides have crucial roles in mammalian fertilization, but the molecules comprising the Ca2+-permeation pathway in sperm motility are poorly understood. Here we describe a putative sperm cation channel, CatSper, whose amino-acid sequence most closely resembles a single, six-transmembrane-spanning repeat of the voltage-dependent Ca2+-channel four-repeat structure. CatSper is located specifically in the principal piece of the sperm tail. Targeted disruption of the gene results in male sterility in otherwise normal mice. Sperm motility is decreased markedly in CatSper-/- mice, and CatSper-/- sperm are unable to fertilize intact eggs. In addition, the cyclic-AMP-induced Ca2+ influx is abolished in the sperm of mutant mice. CatSper is thus vital to cAMP-mediated Ca2+ influx in sperm, sperm motility and fertilization. CatSper represents an excellent target for non-hormonal contraceptives for both men and women.

| S-EPMC8462998 | biostudies-literature

TSNAXIP1 is required for sperm head formation and male fertility.

Project description:PurposeTRANSLIN (TSN) and its binding partner TSNAX have been reported to contribute to a wide spectrum of biological activities including spermatogenesis. TSN accompanies specific mRNA transport in male germ cells through intercellular bridges. A testis-expressed protein TSNAXIP1 was reported to interact with TSNAX. However the role of TSNAXIP1 in spermatogenesis remained unclear. This study aimed to elucidate the role of TSNAXIP1 in spermatogenesis and male fertility in mice.MethodsTSNAXIP1 knockout (KO) mice were generated using the CRISPR-Cas9 system. The fertility, spermatogenesis, and sperm of TSNAXIP1 KO males were analyzed.ResultsTSNAXIP1, and especially its domains, are highly conserved between mouse and human. Tsnaxip1 was expressed in testis, but not in ovary. TSNAXIP1 KO mice were generated, and TSNAXIP1 KO males were found to be sub-fertile with smaller testis and lower sperm count. Although no overt abnormalities were observed during spermatogenesis, lack of TSNAXIP1 induced sperm head malformation, resulting in a unique flower-shaped sperm head. Moreover, abnormal anchorage of the sperm neck was frequently observed in TSNAXIP1 null sperm.ConclusionA testis-expressed gene TSNAXIP1 has important roles in sperm head morphogenesis and male fertility. Moreover, TSNAXIP1 could be a causative gene for human infertility.

| S-EPMC10304756 | biostudies-literature

RSPH6A is required for sperm flagellum formation and male fertility in mice.

Project description:The flagellum is an evolutionarily conserved appendage used for sensing and locomotion. Its backbone is the axoneme and a component of the axoneme is the radial spoke (RS), a protein complex implicated in flagellar motility regulation. Numerous diseases occur if the axoneme is improperly formed, such as primary ciliary dyskinesia (PCD) and infertility. Radial spoke head 6 homolog A (RSPH6A) is an ortholog of Chlamydomonas RSP6 in the RS head and is evolutionarily conserved. While some RS head proteins have been linked to PCD, little is known about RSPH6A. Here, we show that mouse RSPH6A is testis-enriched and localized in the flagellum. Rsph6a knockout (KO) male mice are infertile as a result of their short immotile spermatozoa. Observation of the KO testis indicates that the axoneme can elongate but is disrupted before accessory structures are formed. Manchette removal is also impaired in the KO testis. Further, RSPH9, another radial spoke protein, disappeared in the Rsph6a KO flagella. These data indicate that RSPH6A is essential for sperm flagellar assembly and male fertility in mice.This article has an associated First Person interview with the first author of the paper.

| S-EPMC6198453 | biostudies-literature

ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.

Project description:The mammalian sperm midpiece has a unique double-helical structure called the mitochondrial sheath that wraps tightly around the axoneme. Despite the remarkable organization of the mitochondrial sheath, the molecular mechanisms involved in mitochondrial sheath formation are unclear. In the process of screening testis-enriched genes for functions in mice, we identified armadillo repeat-containing 12 (ARMC12) as an essential protein for mitochondrial sheath formation. Here, we engineered Armc12-null mice, FLAG-tagged Armc12 knock-in mice, and TBC1 domain family member 21 (Tbc1d21)-null mice to define the functions of ARMC12 in mitochondrial sheath formation in vivo. We discovered that absence of ARMC12 causes abnormal mitochondrial coiling along the flagellum, resulting in reduced sperm motility and male sterility. During spermiogenesis, sperm mitochondria in Armc12-null mice cannot elongate properly at the mitochondrial interlocking step which disrupts abnormal mitochondrial coiling. ARMC12 is a mitochondrial peripheral membrane protein and functions as an adherence factor between mitochondria in cultured cells. ARMC12 in testicular germ cells interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3 as well as TBC1D21 and GK2, which are required for mitochondrial sheath formation. We also observed that TBC1D21 is essential for the interaction between ARMC12 and VDAC proteins in vivo. These results indicate that ARMC12 uses integral mitochondrial membrane proteins VDAC2 and VDAC3 as scaffolds to link mitochondria and works cooperatively with TBC1D21. Thus, our studies have revealed that ARMC12 regulates spatiotemporal mitochondrial dynamics to form the mitochondrial sheath through cooperative interactions with several proteins on the sperm mitochondrial surface.

| S-EPMC8017931 | biostudies-literature

GIV/Girdin promotes cell survival during endoplasmic reticulum stress.

Project description:Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced by cells both under normal physiological conditions such as in professional secretory cells and disease states such as cancer, diabetes, and neurodegeneration. Upon facing ER stress, cells activate a conserved signaling pathway called the unfolded protein response (UPR) to restore normal function by halting general protein translation, upregulating expression of chaperones, and promoting ER-associated degradation. However, if the stress is overwhelming and cells are not able to recover within a reasonable time frame, the UPR ultimately commits cells to programmed cell death. How cells make this life-or-death decision remains an exciting yet poorly understood phenomenon. Here, we show that G?-interacting vesicle-associated protein (GIV) aka Girdin plays an important role in promoting cell survival during ER stress. Cells lacking GIV are impaired in activating the pro-survival Akt pathway upon induction of ER stress. These cells also show enhanced levels of the pro-apoptotic transcription factor, CCAAT/enhancer binding protein homologous protein (CHOP) as compared to control cells. Due to decreased pro-survival signals and a concomitant increase in pro-apoptotic signals, GIV-depleted cells show a significant reduction in cell survival upon prolonged ER stress which can be rescued by re-expression of GIV or by directly activating Akt in these cells. Together, this study shows a novel, cytoprotective role for GIV in ER-stressed cells and furthers our understanding of the mechanisms that contribute to cell survival during ER stress.

| S-EPMC6382572 | biostudies-literature

Epididymal protein Rnase10 is required for post-testicular sperm maturation and male fertility.

Project description:Eutherian spermatozoa are dependent on the environment of the proximal epididymis to complete their maturation; however, no specific epididymal factors that mediate this process have so far been identified. Here, we show that targeted disruption of the novel gene Rnase10 encoding a secreted proximal epididymal protein in the mouse results in a binding defect in spermatozoa and their inability to pass through the uterotubal junction in the female. The failure to gain the site of fertilization in the knockout spermatozoa is associated with a gradual loss of ADAM3 and ADAM6 proteins during epididymal transit. In the distal epididymis, these spermatozoa appear to lack calcium-dependent associations with the immobilizing glutinous extracellular material and are released as single, vigorously motile cells that display no tendency for head-to-head agglutination and lack affinity to the oviductal epithelium. In sperm-egg binding assay, they are unable to establish a tenacious association with the zona pellucida, yet they are capable of fertilization. Furthermore, these sperm show accelerated capacitation resulting in an overall in vitro fertilizing ability superior to that of wild-type sperm. We conclude that the physiological role of sperm adhesiveness is in the mechanism of restricted sperm entry into the oviduct rather than in sperm-egg interaction.

| S-EPMC3513842 | biostudies-other

Sperm-Leucylaminopeptidases are required for male fertility as structural components of mitochondrial paracrystalline material in Drosophila melanogaster sperm.

Project description:Drosophila melanogaster sperm reach an extraordinary long size, 1.8 mm, by the end of spermatogenesis. The mitochondrial derivatives run along the entire flagellum and provide structural rigidity for flagellar movement, but its precise function and organization is incompletely understood. The two mitochondrial derivatives differentiate and by the end of spermatogenesis the minor one reduces its size and the major one accumulates paracrystalline material inside it. The molecular constituents and precise function of the paracrystalline material have not yet been revealed. Here we purified the paracrystalline material from mature sperm and identified by mass spectrometry Sperm-Leucylaminopeptidase (S-Lap) family members as important constituents of it. To study the function of S-Lap proteins we show the characterization of classical mutants and RNAi lines affecting of the S-Lap genes and the analysis of their mutant phenotypes. We show that the male sterile phenotype of the S-Lap mutants is caused by defects in paracrystalline material accumulation and abnormal structure of the elongated major mitochondrial derivatives. Our work shows that S-Lap proteins localize and accumulate in the paracrystalline material of the major mitochondrial derivative. Therefore, we propose that S-Lap proteins are important constituents of the paracrystalline material of Drosophila melanogaster sperm.

| S-EPMC6388916 | biostudies-literature

Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility.

Project description:Although glycolysis is highly conserved, it is remarkable that several unique isozymes in this central metabolic pathway are found in mammalian sperm. Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDS) is the product of a mouse gene expressed only during spermatogenesis and, like its human ortholog (GAPD2), is the sole GAPDH isozyme in sperm. It is tightly bound to the fibrous sheath, a cytoskeletal structure that extends most of the length of the sperm flagellum. We disrupted Gapds expression by gene targeting to selectively block sperm glycolysis and assess its relative importance for in vivo sperm function. Gapds(-/-) males were infertile and had profound defects in sperm motility, exhibiting sluggish movement without forward progression. Although mitochondrial oxygen consumption was unchanged, sperm from Gapds(-/-) mice had ATP levels that were only 10.4% of those in sperm from WT mice. These results imply that most of the energy required for sperm motility is generated by glycolysis rather than oxidative phosphorylation. Furthermore, the critical role of glycolysis in sperm and its dependence on this sperm-specific enzyme suggest that GAPDS is a potential contraceptive target, and that mutations or environmental agents that disrupt its activity could lead to male infertility.

| S-EPMC534542 | biostudies-literature

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