Biology subjects

Geyer, C. B.

Publications and source records attributed to Geyer, C. B..

5 recordsLinked to original sources

bioRxiv2026

Sperm development requires TMC5-dependent mechanoresponsive calcium entry

Spermiogenesis, the transformation of round spermatids into streamlined, fertilization-competent sperm, represents cellular morphogenesis at its most extreme. Despite decades of effort, spermiogenesis remains difficult to recapitulate outside the testis, highlighting the importance of cues within the native tissue environment. The nature of these cues, however, remains poorly understood. Here, we discover that mechanical stimulation elicits Ca2+ entry in spermatids and identify transmembrane channel-like protein 5 (TMC5) as a principal mediator of this response. In both mouse and human testes, TMC5 is selectively expressed in spermatids and localized to the plasma membrane. TMC5 associates with TMC7 and calcium- and integrin-binding (CIB) proteins, mirroring TMC-CIB mechanotransduction complexes in sensory organs. Mechanistically, loss of Tmc5 blocks mechanically evoked Ca2+ entry, leading to disruptions in cytoskeletal remodeling and failure of CREM [&tau] dependent transcriptional programs required for spermiogenesis. Thus, TMC5 is required to couple mechanical cues to sperm development, with direct implications for male infertility.

cell biology↗

bioRxiv2026

Actin-related ACTL8 localizes to the nucleus and modulates locus-specific transcription through chromatin regulation

Actin-related proteins (Arps) are evolutionarily ancient and broadly expressed, yet some Arps evolved in mammals and acquired germline-specific expression. Here, we investigate the germline-specific Arp "Actin-like 8" (ACTL8), which is also misexpressed in multiple cancers with unexplored molecular roles. We show that ACTL8 surprisingly localizes to the nucleus of spermatogonia in human testes and breast and lung cancer cells. In breast cancer cells, ACTL8 misexpression alters transcriptional programs primarily in cell migration pathways, and ACTL8 depletion increases migration rate. Mechanistically, we find that ACTL8 interacts with KDM5B, an H3K4 demethylase and transcriptional repressor, and demonstrate that this interaction contributes to changes in migration. Consistent with this, ACTL8 loss increases H3K4me3 at genes associated with migration, indicating transcriptional activation. These findings establish ACTL8 as a novel nuclear Arp that plays a role in KDM5B-mediated transcriptional repression, providing insight into its function in chromatin regulation in cancer and potentially spermatogenesis.

cell biology↗

bioRxiv2025

SIRT7 links H3K36ac epigenetic regulation with genome maintenance in the aging mouse testis

ABSTRACT/SUMMARYReproductive aging is an increasing health concern affecting family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here we found that mammalian Sirtuin 7 (SIRT7) sustains spermatogenesis in an age-dependent manner through the control of histone 3 lysine 36 acetylation (H3K36ac). SIRT7 deficiency in mice resulted in increased levels of H3K36ac in spermatogonia and spermatocytes. In a germ cell line, SIRT7 deficiency disrupted nucleosome stability and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, which are required for continuous sperm production, decreased prematurely in Sirt7-/- mice and showed genome damage accumulation. These changes were concurrent with age-dependent defects in homologous chromosome synapsis and partial meiotic arrest. Taken together, our results indicate that SIRT7 connects H3K36ac epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.

cell biology↗

bioRxiv2023

Cnot3 is required for male germ cell development and spermatogonial stem cell maintenance

The foundation of spermatogenesis and lifelong fertility is provided by spermatogonial stem cells (SSCs). SSCs divide asymmetrically to either replenish their numbers (self-renewal) or produce undifferentiated progenitors that proliferate before committing to differentiation. However, regulatory mechanisms governing SSC maintenance are poorly understood. Here, we show that the CCR4-NOT mRNA deadenylase complex subunit CNOT3 plays a critical role in maintaining spermatogonial populations in mice. Cnot3 is highly expressed in undifferentiated spermatogonia, and its deletion in spermatogonia resulted in germ cell loss and infertility. Single cell analyses revealed that Cnot3 deletion led to the de-repression of transcripts encoding factors involved in spermatogonial differentiation, including those in the glutathione redox pathway that are critical for SSC maintenance. Together, our study reveals that CNOT3 - likely via the CCR4-NOT complex - actively degrades transcripts encoding differentiation factors to sustain the spermatogonial pool and ensure the progression of spermatogenesis, highlighting the importance of CCR4-NOT-mediated post-transcriptional gene regulation during male germ cell development. HighlightsO_LICnot3 is predominantly expressed in undifferentiated spermatogonia, and its expression decreases in later stages. C_LIO_LIConditional deletion of Cnot3 leads to total germ cell loss and male infertility. C_LIO_LICNOT3 represses transcripts encoding factors involved in spermatogonial differentiation. C_LIO_LICNOT3 protects spermatogonial stem cells maintenance via GSH/redox pathway. C_LI Graphical AbstractCnot3 promotes SSC self-renewal by balancing ROS production via the regulation of GSH production O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/562256v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@3afef9org.highwire.dtl.DTLVardef@139cb19org.highwire.dtl.DTLVardef@1450c47org.highwire.dtl.DTLVardef@293300_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2019

Unique Epigenetic Programming Distinguishes Regenerative Spermatogonial Stem Cells in the Developing Mouse Testis

Spermatogonial stem cells (SSCs) both self-renew and give rise to progenitor spermatogonia that enter steady-state spermatogenesis in the mammalian testis. However, questions remain regarding the extent to which SSCs and progenitors represent stably distinct spermatogonial subtypes. Here we provide the first multiparametric integrative analysis of mammalian germ cell epigenomes comparable to that done by the ENCODE Project for >100 somatic cell types. Differentially expressed genes distinguishing SSCs and progenitors showed distinct histone modification patterns as well as differences in distal intergenic low-methylated regions. Motif-enrichment analysis predicted transcription factors that regulate this spermatogonial subtype-specific epigenetic programming, and gene-specific chromatin immunoprecipitation analyses confirmed subtype-specific differences in binding of a subset of these factors to target genes. Collectively, these results suggest that SSCs and progenitors are stably distinct spermatogonial subtypes differentially programmed to either self-renew and maintain regenerative capacity as SSCs, or lose regenerative capacity and initiate lineage commitment as progenitors.

developmental biology↗