Biology subjects

Skinner, W. M.

Publications and source records attributed to Skinner, W. M..

5 recordsLinked to original sources

bioRxiv2026

Oxytocin-like signaling couples reproductive state to intestinal lipid metabolism in aging C. elegans

Oxytocin and vasopressin are endogenous bioactive peptides with conserved roles in reproduction and, more recently recognized, in peripheral lipid metabolism. Whether this signaling system also shapes how reproduction declines with age has not been tested in any animal. Here we show that in C. elegans, the oxytocin/vasopressin-like neuropeptide nematocin restrains reproductive output as animals reach mid-life. Nematocin and its two receptors are produced throughout adult life and peak as reproduction begins to wane. Animals lacking receptor signaling produce more offspring in mid-life, an improvement that reflects better egg quality and fertilization rather than improved embryo survival. This benefit is accompanied by changes in intestinal fat metabolism, the worms equivalent of liver and adipose tissue: nematocin normally limits the activity of a fatty-acid desaturase that is otherwise induced by mating, and it shapes how much yolk reaches developing eggs. The two receptors act through separate routes, one tuning intestinal fat metabolism and the other controlling yolk delivery to the egg. Together, these findings reveal nematocin as a regulator of the intestinal metabolic environment across reproductive age, mirroring the recently described oxytocin-hepatocyte-adipocyte lipid axis in mammals and implicate this conserved signaling system in the coordination of maternal investment during reproductive aging.

physiology↗

bioRxiv2026

In situ molecular architecture of the mammalian sperm nuclear vacuole

Direct identification of macromolecular complexes in their native context remains a major barrier to unbiased biological discovery. This challenge is particularly acute in mammalian sperm nuclei, in which condensed chromatin is interspersed with poorly understood phase-separated compartments termed nuclear vacuoles. Vacuoles are associated with reduced fertilization efficiency, yet their composition remains unclear. Here we combine high-resolution in situ cryo-electron tomography (cryo-ET) with AlphaFold docking to identify vacuole components as proteasomes, the proteasome activator PA200, and ferritin. In situ structures at resolutions up to 3.8 [A] reveal distinct proteasome-PA200 associations and gating states, consistent with a stepwise activation mechanism. Ferritin assemblies exhibit heterogeneous mineralization states and directly contact chromatin. Together, these findings establish the molecular organization of sperm nuclear vacuoles and implicate protein turnover and metal homeostasis in shaping the nuclear landscape, while demonstrating the power of in situ cryo-ET to resolve protein identity and conformational dynamics in native cellular environments.

biochemistry↗

bioRxiv2022

Mitochondrial uncouplers impair human sperm motility without altering ATP content

Sperm motility is necessary for successful fertilization, but there remains controversy about whether human sperm motility is primarily powered by glycolysis or oxidative phosphorylation. To evaluate the plausibility of reducing human sperm mitochondrial ATP production as an avenue for contraceptive development, we treated human sperm with small-molecule mitochondrial uncouplers, which reduce mitochondrial membrane potential by inducing passive proton flow, and evaluated the effects on a variety of physiological processes that are critical for fertilization. We also sought to clarify the subcellular localization of Adenosine Nucleotide Translocator 4 (ANT4), a gamete-specific protein that has been suggested as a contraceptive target. We determined that ANT4 is mitochondrially localized, that induced mitochondrial uncoupling can be partially mediated by the ANT family, and that two uncouplers, Niclosamide Ethanolamine and BAM15, significantly decreased sperm progressive motility. However, these uncouplers did not reduce sperm ATP content or impair other physiological processes, implying that human sperm can rely on glycolysis for ATP production in the absence of functional mitochondria. Thus, since certain mitochondrial uncouplers impair motility through ATP-independent mechanisms, they could be useful ingredients in on-demand, vaginally-applied contraceptives. However, systemically delivered contraceptives that target sperm mitochondria to reduce their ATP production would need to be paired with sperm-specific glycolysis inhibitors. Significance StatementDevelopment of novel contraceptives is critical, since half of all pregnancies are still unplanned, even in developed countries. This high unplanned pregnancy rate contributes to a wide variety of social, environmental, and ecological problems. Impairing human sperm is a way to develop male and unisex contraceptives, but much remains unknown about these unique cells. Here we settle a long-running debate about human sperm metabolism, finding that human sperm can maintain their ATP levels without mitochondrial oxidative phosphorylation. This finding will help focus future contraceptive development efforts. We also identify the potential use of an FDA-approved compound (Niclosamide) as a motility-impairing ingredient in spermicides and correct the misunderstood subcellular localization of an existing contraceptive target, Adenosine Nucleotide Translocator 4.

cell biology↗

bioRxiv2022

Human sperm TMEM95 binds eggs and facilitates membrane fusion

Tmem95 encodes a sperm acrosomal membrane protein, whose knockout has a male-specific sterility phenotype in mice. How TMEM95 plays a role in membrane fusion of sperm and eggs has remained elusive. Here, we utilize a sperm penetration assay as a model system to investigate the function of human TMEM95. We show that human TMEM95 binds to hamster egg membranes, providing evidence for a TMEM95 receptor on eggs. Using X-ray crystallography, we reveal an evolutionarily conserved, positively charged region of TMEM95 as a putative receptor-binding surface. Amino-acid substitutions within this region of TMEM95 ablate egg-binding activity. We identify monoclonal antibodies against TMEM95 that reduce the number of human sperm fused with hamster eggs in sperm penetration assays. Strikingly, these antibodies do not block binding of sperm to eggs. Taken together, these results provide strong evidence for a specific, receptor-mediated interaction of sperm TMEM95 with eggs and suggest that this interaction may have a role in facilitating membrane fusion. Significance statementMembrane fusion of sperm and eggs is pivotal in sexual reproduction. Tmem95 knockout mice show male-specific sterility, but it was unknown how sperm TMEM95 facilitates membrane fusion with eggs. We show here that human TMEM95 binds eggs. Our crystal structure of TMEM95 suggests a region where this binding may occur. We develop monoclonal antibodies against TMEM95 that impair sperm-egg fusion but do not block sperm-egg binding. Thus, we propose that there is a receptor-mediated interaction of sperm TMEM95 with eggs, and that this interaction may have a direct role in membrane fusion. Our work suggests avenues for the identification of the TMEM95 egg receptor and may enable the development of infertility treatments and contraceptives for humans.

developmental biology↗

bioRxiv2022

In situ cryo-electron tomography reveals the asymmetric architecture of mammalian sperm axonemes

The flagella of mammalian sperm display non-planar, asymmetric beating, in contrast to the planar, symmetric beating of flagella from sea urchin sperm and unicellular organisms. The molecular basis of this difference is unclear. Here, we perform in situ cryo-electron tomography of mouse and human sperm axonemes, providing the highest resolution structural information to date. Our subtomogram averages reveal mammalian sperm- specific protein complexes within the outer microtubule doublets, the radial spokes and nexin-dynein regulatory complexes. The locations and structures of these complexes suggest potential roles in enhancing the mechanical strength of mammalian sperm axonemes and regulating dynein-based axonemal bending. Intriguingly, we find that each of the nine outer microtubule doublets is decorated with a distinct combination of sperm- specific complexes. We propose that this asymmetric distribution of proteins differentially regulates the sliding of each microtubule doublet and may underlie the asymmetric beating of mammalian sperm.

biophysics↗