Lumicrine signaling: Extracellular regulation of sperm maturation in the male reproductive tract lumen

Kiyozumi, Daiji

doi:10.1111/gtc.13066

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…Neural EGF-like like 2 (NELL2) and the NELL2-interacting cofactor for lumicrine signaling (NICOL) serve as ligand proteins secreted by the germ cells within the testes into the reproductive tract lumen [ 9 , 10 ]. These ligand proteins traverse the reproductive tract lumen to reach the epididymis, where they bind to the receptor-type tyrosine kinase ROS1 expressed in the IS [ 11 – 13 ]. Upon ligand binding, ROS1 activates downstream intracellular signaling pathways [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of NELL2/NICOL-ROS1 lumicrine signaling-related molecules in the human male reproductive tract

Kiyozumi

2024

Reprod Biol Endocrinol

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The maturation of spermatozoa is a regulated process, influenced by genes expressing essential secreted proteins in the proximal epididymis. Recent genetic studies in rodents have identified the non-sex steroidal molecular signals that regulate gene expression in the proximal epididymis. Germ cells in the testis secrete ligand proteins into the seminiferous tubule lumen The ligand proteins travel through the male reproductive tract lumen to the epididymis, where they bind to receptors, triggering the differentiation of the luminal epithelium for sperm maturation. It is, however, not fully unveiled if such a testis-epididymis trans-luminal signaling mechanism exists in other species, especially humans. In the present study, the rodent-type testis-epididymis trans-luminal signaling in the human male reproductive tract was evaluated in a step-by-step manner by analyzing testis and epididymis gene expression and signaling mediator protein function. There was a significant correlation between the epididymal expressions of mouse genes upregulated by the trans-luminal signaling and those of their human orthologs, as evaluated by the correlation coefficient of 0.604. The transcript expression of NELL2 and NICOL encoding putative ligand proteins was also observed in human testicular cells. In vitro experiments demonstrated that purified recombinant human NELL2 and NICOL formed a molecular complex with similar properties to rodent proteins, which was evaluated by a dissociation equilibrium constant of 110 nM. Recombinant human NELL2 also specifically bound to its putative receptor human ROS1 in vitro. Collectively, these findings suggest that the rodent-type testis-epididymis secreted signaling mechanism is also possible in the human male reproductive tract.

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Section: Introductionmentioning

confidence: 99%

Expression of NELL2/NICOL-ROS1 lumicrine signaling-related molecules in the human male reproductive tract

Kiyozumi

2024

Reprod Biol Endocrinol

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“…The epididymis, a highly coiled epithelial duct, is part of the sperm transport route. After production in the testis, morphologically complete, but functionally immature, testicular spermatozoa are transported through the efferent duct toward the epididymis, where they undergo further functional maturation necessary for their full fertilizing ability [ 1 , 2 , 3 , 4 ]. If spermatozoa are not properly matured by the epididymis, they will not be able to acquire the cellular functions necessary for fertilization, eventually resulting in a significant decrease in male reproductive ability.…”

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“…Recent studies have revealed the molecular mechanisms underlying lumicrine signaling [ 2 , 13 , 15 , 16 , 17 , 18 , 19 ]. In the testes, germ cells located inside seminiferous tubules secrete lumicrine factor proteins, such as neural epidermal growth factor–like like 2 (NELL2) and NELL2-interacting cofactor for lumicrine signaling (NICOL), into the seminiferous lumen.…”

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Busulfan administration replicated the characteristics of the epididymal initial segment observed in mice lacking testis-epididymis lumicrine signaling

KIYOZUMI

2024

Journal of Reproduction and Development

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The physiological functions of the mammalian epididymis are typically regulated by the testes. In addition to sex steroids secreted by testicular Leydig cells, which act on the epididymis in an endocrine manner, there is a non-sex-steroidal signaling pathway known as the lumicrine pathway. This lumicrine signaling pathway involves ligand proteins secreted from germ cells within the testicular seminiferous tubules traversing the male reproductive tract, which induce epithelial differentiation in the epididymis. These findings prompted an inquiry into whether treatments influencing testis physiology can disrupt epididymal function by interfering with testis-epididymis communication. Busulfan, an alkylating agent commonly used to deplete testicular germ cells in reproductive biology, has not been sufficiently explored because of its effects on the epididymis. This study investigated the effects of busulfan administration on the proximal epididymis using histological and transcriptomic analyses. Notably, busulfan, as opposed to the vehicle dimethyl sulfoxide (DMSO), altered the morphology of the initial segment of the epididymis, leading to a reduction in the cell height of the luminal epithelium. RNA sequencing identified 185 significantly downregulated genes in the proximal epididymis of busulfan-administered mice compared to DMSO-administered mice. Comparative transcriptome analyses revealed similarities between the epididymal transcriptome of busulfan-administered mice and lumicrine-deficient mice, such as efferent-duct-ligated W / Wv and Nell2 -/- mice. However, this differed from that of bilaterally orchidectomized mice, in which both the endocrine and lumicrine signaling pathways were simultaneously ablated. Collectively, these results suggested that the harmful effects of busulfan on the proximal epididymis are secondary consequences of the ablation of testis-epididymis lumicrine signaling.

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Cellular mechanism underlying leptin‐induced anion secretion of rat epididymal epithelial cells

Gao,

Liu,

Chen

et al. 2024

Andrology

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BackgroundA large number of studies have shown that leptin plays an important role in the regulation of fertility via the hypothalamus‐pituitary‐gonad axis. However, its peripheral function in epididymis was still elusive.ObjectiveThe purpose of this study was to determine the pro‐secretion effect of leptin on the rat epididymal epithelium.Materials and methodsIn the present study, real‐time quantitative polymerase chain reaction, western blot, and immunohistochemical analysis were employed to detect the expression pattern of leptin receptors in rat epididymis. The pro‐secretion effect of leptin on epididymal epithelial cells was measured by short‐circuit current, and the prostaglandin E2 and cyclic adenosine monophosphate level was evaluated by enzyme‐linked immunosorbent assay.ResultsWe verified that the leptin receptor was located on the epididymal epithelium, with a relatively high expression level in corpus and cauda epididymis. Ussing chamber experiments showed that leptin stimulated a significant rise of the short‐circuit current in rat epididymal epithelial cells, which could be abolished by the specific leptin receptor antagonist peptide Allo‐aca, or by removing the ambient Cl− and HCO3−. Furthermore, the leptin‐stimulated short‐circuit current response could be abrogated by blocking the apical cystic fibrosis transmembrane regulator or the basolateral Na+‐K+‐2Cl− cotransporter. Our pharmacological experiments manifested that interfering with the prostaglandin H synthase‐2‐prostaglandin E2‐EP2/EP4‐adenylate cyclase pathways could significantly blunt the cystic fibrosis transmembrane regulator‐mediated anion secretion induced by leptin. The enzyme‐linked immunosorbent assay demonstrated that leptin could induce a substantial increase in prostaglandin E2 release and cyclic adenosine monophosphate synthesis of primary cultured rat cauda epididymal epithelial cells. Our data also suggested that JAK2, ERK, and PI3K‐dependent phosphorylation may be involved in the activation of prostaglandin H synthase‐2 and the subsequent prostaglandin E2 production.ConclusionsThe present study demonstrated the pro‐secretion function of leptin in rat epididymal epithelium via the activation of cystic fibrosis transmembrane regulator and Na+‐K+‐2Cl− cotransporter, which was dependent on the paracrine/autocrine prostaglandin E2 stimulated EP2/EP4‐adenylate cyclase pathways, and thus contributed to the formation of an appropriate microenvironment essential for sperm maturation.

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Lumicrine signaling: Extracellular regulation of sperm maturation in the male reproductive tract lumen

Cited by 4 publications

References 26 publications

Expression of NELL2/NICOL-ROS1 lumicrine signaling-related molecules in the human male reproductive tract

Expression of NELL2/NICOL-ROS1 lumicrine signaling-related molecules in the human male reproductive tract

Busulfan administration replicated the characteristics of the epididymal initial segment observed in mice lacking testis-epididymis lumicrine signaling

Cellular mechanism underlying leptin‐induced anion secretion of rat epididymal epithelial cells

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