Biology subjects

Keyes, W. M.

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

5 recordsLinked to original sources

bioRxiv2025

Developmental senescence profiling reveals Eda2r as a common mediator in the core senescence program

Cellular senescence is a distinct state of stable cell-cycle arrest coupled to a dynamic secretory phenotype. Although transient senescence contributes to embryonic development and regeneration, its relationship to the chronic forms associated with damage and aging is unclear. Here, we generated a p21-reporter mouse to isolate and transcriptionally profile senescent cells in Apical Ectodermal Ridge of the developing limb. Comparative analysis of these cells with diverse in vitro and in vivo senescence models revealed a conserved gene program encompassing canonical markers and regulators, with previously unassociated factors. Among these, ectodysplasin A2 receptor (Eda2r) emerged as a critical modulator required for senescence-associated transcriptional and functional features. Our findings define a shared molecular framework linking developmental and pathological senescence and identify conserved effectors such as Eda2r as potential targets for therapeutic modulation of senescent cell function.

cell biology↗

bioRxiv2025

Senescent cells exhibit features of developmental signaling centres

Cellular senescence is a state that contributes to tissue patterning during development and tissue repair, but which becomes misregulated in ageing and disease. The senescence-associated secretory phenotype (SASP) mediates many of the context-dependent effects, yet its molecular composition and evolutionary origins remain incompletely understood. Here, we characterize the SASP signature of developmental senescent cells and find that it is enriched for genes encoding major developmental signaling pathways. Integrative analyses of in vitro and in vivo transcriptomes reveal that human and mouse senescent cells across diverse contexts consistently activate these developmental programs, with key morphogens constituting conserved SASP components. Functionally, we show that the SASP is sufficient to induce the expression of central developmental genes and transcription factors across multiple cell types. These findings show that senescent cells resemble developmental signaling centers and uncover developmental signaling reactivation as an evolutionarily conserved feature of senescence, providing conceptual insight into its physiological functions and its pathological impact during ageing.

cell biology↗

bioRxiv2021

Valproic acid induces p19Arf-mediated cellular senescence to cause neurodevelopmental defects

Timely induction of cellular senescence is important during embryonic development and tissue repair, while aberrant activation contributes to many age-related diseases. However, whether abnormal induction of senescence in the embryo contributes to developmental defects remains unclear. To explore this, we investigated the clinically significant model of Valproic acid- (VPA) induced developmental defects. VPA is a widely prescribed drug to treat epilepsy, bipolar disorder and migraine. If taken during pregnancy however, exposure to the developing embryo can cause birth defects, cognitive impairment and Autism-Spectrum Disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of drug exposure, including exencephaly, microcephaly and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial cells. Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but surprisingly, not exencephaly and spinal defects. Together, these findings uncover how misregulated senescence in neuroepithelial cells can contribute to developmental defects.

developmental biology↗

bioRxiv2021

Cell cycle gene regulation dynamics revealed by RNA velocity and deep-learning

The cell cycle is a fundamental process of life, however, a quantitative understanding of gene regulation dynamics in the context of the cell cycle is still far from complete. Single-cell RNA-sequencing (scRNA-seq) technology gives access to its dynamics without externally perturbing the cell. Here, we build a high-resolution map of the cell cycle transcriptome based on scRNA-seq and deep-learning. By generating scRNA-seq libraries with high depth, in mouse embryonic stem cells and human fibroblasts, we are able to observe cycling patterns in the unspliced-spliced RNA space for single genes. Since existing methods in scRNA-seq are not efficient to measure cycling gene dynamics, we propose a deep learning approach to fit these cycling patterns sorting single cells across the cell cycle. We characterize the cell cycle in asynchronous pluripotent and differentiated cells identifying major waves of transcription during the G1 phase and systematically study the G1-G0 transition where the cells exit the cycle. Our work presents to the scientific community a broader understanding of RNA velocity and cell cycle maps, that we applied to pluripotency and differentiation. Our approach will facilitate the study of the cell cycle in multiple cellular models and different biological contexts, such as cancer and development.

systems biology↗

bioRxiv2019

Senolytic treatment targets aberrant p21-expression to restore liver regeneration in adult mice

Young mammals possess a limited regenerative capacity in tissues such as the liver, heart and limbs, but which is quickly lost upon maturation or transition to adulthood. Chronic cellular senescence is a known mediator of decreased tissue function in aging and disease. Here we investigated whether senescence plays a role in the progressive loss of liver regenerative capacity that develops in young adult mice. We find that following partial hepatectomy, the senescence markers p21, p16Ink4a and p19Arf become dynamically expressed at an age when regenerative capacity decreases. In addition, we demonstrate that treatment with a senescence-inhibiting drug improves regenerative capacity, through targeting of aberrant p21 expression. Surprisingly, we also find that the senescence marker p16Ink4a is expressed in a different cell-population to p21, and is unaffected by senescence targeting. This work suggests that senescence may initially develop as a heterogeneous cellular response, and that treatment with senolytic drugs may aid in promoting organ regeneration.

cell biology↗