Biology subjects

Derry, B.

Publications and source records attributed to Derry, B..

4 recordsLinked to original sources

bioRxiv2025

A stress-dependent postembryonic role for the core CPA factor CFIM-1 in germline integrity

Post-transcriptional processing of pre-mRNAs generates a diversity of 3 UTR transcript isoforms that can vary in their function and stability. The differential enrichment of transcript isoforms has been implicated in diseases ranging from cancer to neurodevelopmental disorders. However, the post-embryonic developmental roles of the core ensemble of cleavage and polyadenylation (CPA) factors that mediate these post-transcriptional changes remain poorly characterized. Here, we report a stress- dependent role for the core CPA factor CFIM-1 in germline integrity in Caenorhabditis elegans. Total loss-of-function of cfim-1 elicits a temperature-sensitive sterile phenotype in hermaphrodites. These changes in brood size are accompanied by broad sperm, oocyte and germline morphology defects. Surveying the transcriptome of cfim-1(lf) worms, we uncover changes in transcript isoform abundance for dozens of genes with known functions related to the development and maintenance of these structures, consistent with a model in which post-transcriptional regulation of target genes via cfim- 1 is crucial to the development and maintenance of germline integrity. Our findings collectively define a novel post-embryonic role for a core CPA factor in tissue-specific development.

developmental biology↗

bioRxiv2024

TSC22D, WNK and NRBP gene families exhibit functional buffering and evolved with Metazoa for macromolecular crowd sensing

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. Myriad redundancies have evolved across all facets of osmosensing in metazoans, including among water and ion transporters, regulators of cellular morphology, and macromolecular crowding sensors, hampering efforts to gain a clear understanding of how cells respond to rapid water loss. In this study, we harness the power of gene co-essentiality analysis and genome-scale CRISPR-Cas9 screening to identify an unappreciated relationship between TSC22D2, WNK1 and NRBP1 in regulating cell volume homeostasis. Each of these genes have paralogs and are functionally buffered for macromolecular crowd sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK and NRBP family members physically associate into cytoplasmic biocondensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans reveals that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is concomitant with rapid IDR length expansion in WNK family kinases. Our study identifies functions for unrecognized components of the cell volume sensing machinery and reveals that TSC22D, WNK and NRBP genes evolved as cytoplasmic crowding sensors in metazoans to co-regulate rapid cell volume changes in response to osmolarity.

cell biology↗

bioRxiv2024

CDK-4 regulates nucleolar size and anabolic metabolism as a fitness tradeoff in C. elegans

An outstanding question in biology concerns mechanisms of size control in organs, cells, and organelles. Size impacts metabolic efficiency, surface area-to-volume ratio, and environmental adaptation, which are all required for optimal function. Cyclin-dependent kinase 4 (CDK4), traditionally recognized for its role in cell cycle progression, has gained increasing support for cell cycle-independent roles. Previously, we described a mechanism of cell size control involving a CDK4 and p38 MAPK circuitry that dictates target cell size. In this study, we target the CDK4/6 ortholog CDK-4 in the nematode worm Caenorhabditis elegans to describe functional consequences of changing biological size in vivo. Our data suggest that CDK-4 regulates nucleolar size and anabolic metabolism independent from cell cycle progression. When size and metabolism are increased, we report enhanced thermotolerance early in life but accelerated aging and reduced longevity late in life, suggesting a novel function of CDK-4 in somatic maintenance and organism health.

cell biology↗

bioRxiv2020

Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38

While molecules that promote the growth of animal cells have been identified, the following question remains: How are growth promoting pathways regulated to specify a characteristic size for each of the different cell types? In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints - mechanisms that restrict cell cycle progression from cells that are smaller than their target size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cells actual size and cells target size. In the present study, we materialize this conceptual distinction by describing experimental assays that discriminately quantify a cells target size value. With these assays, we show that a cells size and target size are distinct phenotypes that are subject to different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cells target size value is regulated by other pathways including FGFR3, ROCK2, and CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, rapamycin does not change the target size that is required for the G1/S transition. The CDK4/Rb pathway has been previously proposed as a putative regulator of target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size were not validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to dial higher and lower levels of CDK4 activity. These measurements identified functions of CDK4 on target size that are distinct from other G1 CDKs. Using C. elegans, we further demonstrate that these influences of CDK4 on size determination function in vivo. Finally, we propose a model whereby mTORC1, p38, and CDK4 cooperate in a manner that is analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostat dial that sets the critical target size associated with cell size homeostasis.

cell biology↗