bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.06.10.495573

Human sperm TMEM95 binds eggs and facilitates membrane fusion

Tang, S.·Lu, Y.·Skinner, W. M.·Sanyal, M.·Lishko, P. V.·Ikawa, M.·Kim, P. S.
View original source ↗Export metadata ↓

Abstract

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.

Source connections

Explore related subjects

developmental biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Tang, S., Lu, Y., Skinner, W. M., Sanyal, M., Lishko, P. V., Ikawa, M., Kim, P. S.. 2022-06-10. Human sperm TMEM95 binds eggs and facilitates membrane fusion. https://doi.org/10.1101/2022.06.10.495573

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Alveolar and airway progenitors converge on an epigenetically encoded profibrotic state

During organ regeneration, epithelial transitional states arise from progenitors and instruct the mesenchyme to remodel the extracellular matrix. However, the identity of the progenitors, the mechanisms underlying this transition, and why these states persist in tissue fibrosis often remain elusive. Here, using lineage tracing in mice, we show that the profibrotic KRT5-/KRT17+ state in pulmonary fibrosis arises convergently from alveolar type (AT) 2 and airway secretory cells. AT1 cells generate neither KRT5-/KRT17+ nor AT2 cells. TGF-{beta}/SMAD3 acts through KMT2A and p300 to epigenetically reprogram human AT2 cells into the KRT5-/KRT17+ state. In human pulmonary fibrosis, KRT5-/KRT17+ cells slough off, and transitional cells re-epithelialize the denuded basement membrane. Transcriptionally convergent states arise in injured kidney, skin, and intestine. This work reframes fibrogenesis as the accumulation of a conserved profibrotic transitional state via ongoing turnover, not persistence alone, and nominates the state transition and its epigenetic regulators as therapeutic targets.

developmental biology↗
bioRxiv2026

Dynamic mechanical sorting biases niche occupancy and lineage outcome during development of bilayered glandular epithelia

Tissue compartmentalization into basal and luminal domains is a hallmark of glandular epithelia, yet how fate boundaries are established and stabilized during dynamic morphogenesis remains a major unresolved question. Here, using mouse embryonic explants, organoids, quantitative live imaging and genetic perturbations, we show that basal-luminal compartmentalization is not maintained by fixed boundaries, but through continuous positional corrections. We show that differences in cellular adhesion and actomyosin contractility drive these positional corrections by promoting active cell sorting. We further find that these mechanical differences influence lineage specification by controlling cell positioning rather than directly instructing cell fate. Before commitment, mosaic, but not uniform, perturbation of cell mechanics alters niche occupancy and biases lineage outcome, indicating that relative mechanical properties determine access to fate-instructive niches. Conversely, perturbation of Notch and YAP remodels compartment-specific mechanical properties and cell-positioning dynamics, revealing a reciprocal coupling between lineage state and mechanical sorting. Conservation of this mechanism across four glandular epithelia of distinct origins and functions identifies dynamic mechanical sorting as a general strategy for maintaining robust tissue compartmentalization during the extensive growth and cellular rearrangements of branching morphogenesis.

developmental biology↗
bioRxiv2026

Unbiased lineage tracing across the adipose organ decouples developmental origin from anatomical and transcriptomic identities

The developmental origins of individual adipose depots and whether embryonic lineage dictates adult function remain unresolved. Here, we apply in utero CRISPR-mediated barcoding lineage tracing to construct the first unbiased clonal map of adipose organ development in mice. The developmental hierarchy we uncover challenges several conventions. Remarkably, interscapular brown fat, used as the prototypical brown fat, is the most developmentally isolated brown fat; depots sharing Myf5/Pax3 lineage markers fail to cluster together; mesenteric white fat shares unexpected high clonal ancestry with brown fats despite a radically divergent transcriptome; and subcutaneous white adipose tissues converge transcriptomically despite distant developmental origins. These findings call for a reinterpretation of single-marker lineage tracing data across the adipose organ and propose that adipose depot identity is not solely encoded by embryonic lineage but is substantially shaped by the anatomical niche.

developmental biology↗