Biology subjects

Stelzer, G.

Publications and source records attributed to Stelzer, G..

4 recordsLinked to original sources

bioRxiv2025

Cell surface ATP6V1B2 marks a subset of persistent senescent cells with increased resistance to apoptosis

Accumulation of senescent cells promotes ageing and age-related diseases. While senescent cells are heterogenous and increasingly persistent in vivo with age, the mechanisms underlying their heterogeneity, resistance to apoptosis, and tissue accumulation remain insufficiently understood. Here we report that in response to DNA damage, a subset of senescent cells upregulates the v-type ATPase subunit, ATP6V1B2 (V1B2) on the cell surface. This upregulation is associated with altered lysosomal activity and changes in intracellular pH. Heterogeneity of senescent cells marked by cell surface V1B2 (csV1B2) is present in naturally occurring senescent cells within both ageing and fibrotic lungs. Senescent cells expressing csV1B2 show an age-independent transcriptional signature associated with DNA repair and resistance to apoptosis. Consistent with this, we show that csV1B2 expression correlates with senescent cell resistance to ABT-737-induced apoptosis in culture. Our study identifies a subset of senescent cells, marked by csV1B2, with a distinct signature of apoptosis resistance. Understanding the functional heterogeneity of senescent cells and the mechanisms accountable for persistence of specific subpopulations in tissues may facilitate the development of improved senotherapeutic strategies for age-related diseases.

cell biology↗

bioRxiv2025

Aberrant inheritance of extrachromosomal DNA amplifications promotes cancer evolution

Gene amplification in the form of extrachromosomal DNA (ecDNA) is a frequent driver in multiple cancer types. As ecDNA lack centromeres, their mitotic segregation does not follow traditional inheritance principles. However, the mechanisms that govern ecDNA fate following mitosis remain unclear. We found that ecDNA undergo numerical and structural optimization under increased selective pressure, with mitotic chromosomal tethering, or detachment, dictating ecDNA fate. When tethered, ecDNA aggregates promote uneven distribution into the newly formed daughter cells, thereby driving inter-cellular numerical heterogeneity and rapid increase of amplification under selective pressure. Mitotically detached ecDNA frequently encapsulate within micronuclei of variable size and content that appear to be highly fragile. Strikingly, ecDNA enclosed in very small micronuclei, which we term nanonuclei, are being actively degraded through autophagy. Together with ongoing structural rearrangements, nanonuclear ecDNA degradation promotes their structural evolution, which facilitates cancer cell adaptation. Our work highlights ecDNA aggregation, micronucleation, and degradation, as pivotal events in directing cancer genome evolution trajectories.

cancer biology↗

bioRxiv2024

A Blueprint of Sex-Specific Neuronal Regulation in the C. elegans Nervous System at Single-Cell Resolution

Sex-specific behaviors are often attributed to differences in neuronal wiring and molecular composition, yet how genetic sex shapes the molecular architecture of the nervous system at the individual neuron level remains unclear. Here, we use single-cell RNA sequencing to profile the transcriptome of sex-shared neurons in adult Caenorhabditis elegans males and hermaphrodites. We uncover widespread molecular dimorphism across the nervous system, including in previously unrecognized neuron-types such as the touch receptors. Neuropeptides and signaling-related genes exhibit strong sex-biased expression, particularly in males, reinforcing the notion that neuropeptides are crucial for diversifying connectome outputs. Despite these differences, neurotransmitter identities remain largely conserved, indicating that functional dimorphism arises through modulatory, not identity-defining, changes. We show that sex-biased expression of neurotransmitter-related genes correlates with bias in outgoing synaptic connectivity and identify regulatory candidates for synaptic wiring, including both shared and sex-specific genes. This dataset provides a molecular framework for understanding how subtle regulatory differences tune conserved circuits to drive sex-specific behaviors.

neuroscience↗

bioRxiv2023

Sex-Specific Developmental Gene Expression Atlas Unveils Dimorphic Gene Networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we created a comprehensive gene expression atlas for both sexes of the nematode Caenorhabditis elegans across development. By comparing the transcriptome of pure populations of hermaphrodites and males from early larval stages to adulthood, we discovered numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and GPCRs. We identified INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually-dimorphic roles in temperature sensation, survival in cold temperatures, resilience against high hydrogen peroxide levels, and dauer entry, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans, which will facilitate research into the genetic regulation of the sexual development of other organisms. Furthermore, it highlights conserved candidate genes that may underlie the sexually-dimorphic manifestation of different human diseases.

neuroscience↗