Biology subjects

Savage-Dunn, C.

Publications and source records attributed to Savage-Dunn, C..

8 recordsLinked to original sources

bioRxiv2025

BMP-Dependent Mobilization of Fatty Acid Metabolism Promotes Caenorhabditis elegans Survival on a Bacterial Pathogen

The Bone Morphogenetic Proteins (BMPs) are secreted peptide ligands of the Transforming Growth Factor beta (TGF-{beta}) family, initially identified for their roles in development and differentiation across animal species. They are now increasingly recognized for their roles in physiology and infectious disease. In the nematode Caenorhabditis elegans, the BMP ligand DBL-1 controls fat metabolism and immune response, in addition to its roles in body size regulation and development. DBL-1 regulates classical aspects of innate immunity, including the induction of anti-microbial peptides. We theorized that BMP-dependent regulation of fat metabolism could also promote resilience against microbial pathogens. We found that exposure to a bacterial pathogen alters total fat stores, lipid droplet dynamics, and lipid metabolism gene expression in a BMP-dependent manner. We further showed that fatty acid desaturation plays a major role in survival on a bacterial pathogen, while fatty acid {beta}-oxidation plays a more minor role. We conclude that C. elegans mobilizes fatty acid metabolism in response to pathogen exposure to promote survival. Our investigation provides a framework to study potential metabolic interventions that could support therapeutics that are complementary to antibiotic strategies.

physiology↗

bioRxiv2024

Genome-wide analysis of Smad and Schnurri transcription factors in C. elegans demonstrates widespread interaction and a function in collagen secretion

Smads and their transcription factor partners mediate the transcriptional responses of target cells to secreted ligands of the Transforming Growth Factor-{beta} (TGF-{beta}) family, including those of the conserved bone morphogenetic protein (BMP) family, yet only a small number of direct target genes have been well characterized. In C. elegans, the BMP2/4 ortholog DBL-1 regulates multiple biological functions, including body size, via a canonical receptor-Smad signaling cascade. Here, we identify functional binding sites for SMA-3/Smad and its transcriptional partner SMA-9/Schnurri based on ChIP-seq peaks (identified by modEncode) and expression differences of nearby genes identified from RNA-seq analysis of corresponding mutants. We found that SMA-3 and SMA-9 have both overlapping and unique target genes. At a genome- wide scale, SMA-3/Smad acts as a transcriptional activator, whereas SMA-9/Schnurri direct targets include both activated and repressed genes. Mutations in sma-9 partially suppress the small body size phenotype of sma-3, suggesting some level of antagonism between these factors and challenging the prevailing model for Schnurri function. Functional analysis of target genes revealed a novel role in body size for genes involved in one-carbon metabolism and in the endoplasmic reticulum (ER) secretory pathway, including the disulfide reductase dpy-11. Our findings indicate that Smads and SMA-9/Schnurri have previously unappreciated complex genetic and genomic regulatory interactions that in turn regulate the secretion of extracellular components like collagen into the cuticle to mediate body size regulation.

genomics↗

bioRxiv2023

TGF-β Ligand Interactions in the Response of Caenorhabditis elegans to Bacterial Pathogens

The Transforming Growth Factor beta (TGF-{beta}) family consists of numerous secreted peptide growth factors that play significant roles in cell function, tissue patterning, and organismal homeostasis, including wound repair and immunity. Typically studied as homodimers, these ligands have the potential to diversify their functions through ligand interactions that are synergistic, cooperative, additive, and/or antagonistic. In the nematode Caenorhabditis elegans, there are only five TGF-{beta} ligands, providing an opportunity to dissect ligand interactions in fewer combinations than in vertebrates. As in vertebrates, these ligands can be divided into bone morphogenetic protein (BMP) and TGF-{beta}/Activin subfamilies that predominantly signal through discrete signaling pathways. The BMP subfamily ligand DBL-1 has been well studied for its role in the innate immune response in C. elegans. Here we show that all five TGF-{beta} ligands play a role in the immune response. We also demonstrate that multiple TGF-{beta} ligands act cooperatively as part of this response. We show that the two BMP-like ligands - DBL-1 and TIG-2 - function independently of each other in the immune response, while TIG-2/BMP and the TGF-{beta}/Activin-like ligand TIG-3 function cooperatively. Structural modeling supports the potential for TIG-2 and TIG-3 to form heterodimers. Finally, we show that canonical DBL-1/BMP receptor and Smad signal transducers function in the response to bacterial pathogens, while components of the DAF-7 TGF-{beta}/Activin signaling pathway do not play a role in survival. These results demonstrate a novel potential for BMP and TGF-{beta}/Activin subfamily ligands to interact, and may provide a mechanism for distinguishing the developmental and homeostatic functions of these ligands from an acute response such as the innate immune response to bacterial pathogens.

physiology↗

bioRxiv2023

BMP signaling in the C. elegans immune response to bacterial pathogen regulates anti-microbial peptide expression through cell non-autonomous activity

Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In C. elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and post-developmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens. Significance StatementO_LIInnate immunity is the first line of defense against pathogens. Conserved cell signaling pathways are known to be involved in host-pathogen response, but how they coordinate a systemic response is less well understood. C_LIO_LIIn the nematode C. elegans, bone morphogenetic protein (BMP) signaling is required for survival on pathogenic bacteria. Using transgenic strains, the authors identify a major role for a specific organ, the pharynx, in BMP-dependent survival. C_LIO_LIThese findings demonstrate that an organ can serve as a pathogen sensor to trigger multiple modes of response to bacterial pathogens, include a barrier response and regulation of anti-microbial peptide expression. C_LI

physiology↗

bioRxiv2019

Mechanism of Interaction of BMP and Insulin Signaling in C. elegans Development and Homeostasis

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not known. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing two additional IIS functions, dauer formation and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

cell biology↗

bioRxiv2019

Feedback regulation of BMP signaling by C. elegans cuticle collagens

Cellular responsiveness to environmental cues, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level of dbl-1 transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.

developmental biology↗

bioRxiv2017

C. elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling

Metabolic homeostasis is coordinately controlled by diverse inputs, which must be understood to combat metabolic disorders. Here we introduce DBL-1, the C. elegans BMP2/4 homolog, as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL 1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling (IIS) in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through inter-organ signaling to IIS, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

cell biology↗

bioRxiv2017

Caenorhabditis elegans BMP Transcriptional ProgramImplicates Collagen Genes in Body Size Regulation

Body size is a tightly regulated phenotype in metazoans that is dependent on both intrinsic and extrinsic factors. While signaling pathways such as insulin, Hippo, and myostatin are known to control organ and body size, the downstream effectors that mediate their effects are still poorly understood. In the nematode C. elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. DBL-1, the BMP-related ligand, is secreted by neurons and body wall muscle, and acts as a dose-dependent regulator of body size. We investigated the transcriptional network through which the DBL-1/BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. Here we demonstrate that cuticle collagen genes can act as positive regulators (col-41), dose-sensitive regulators (rol-6), and negative regulators (col-141, col-142) of body size. Moreover, we show requirement of DBL-1/BMP signaling for stage-specific expression of cuticle collagen genes. We used chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) and electrophoretic mobility shift assays to show that the Smad signal transducers directly associate with conserved Smad binding elements in regulatory regions of col-141 and col-142, but not of col-41. Hence, cuticle collagen genes are directly and indirectly regulated via the DBL-1/BMP pathway. These results provide the first direct regulatory link between this conserved signaling pathway and the collagen genes that act as its downstream effectors in body size regulation. Since collagen mutations and misregulation are implicated in numerous human genetic disorders and injury sequelae, understanding how collagen gene expression is regulated has broad implications.\n\nAuthor SummaryBody size in humans and other animals is determined by the combined influence of genetic and environmental factors. Failure to regulate growth and body size appropriately can lead to a variety of functional impairments and reduced fitness. Progress has been made in identifying genetic determinants of body size, but these have not often been connected into functional pathways. In the nematode model Caenorhabditis elegans, single gene mutations in the BMP signaling pathway have profound effects on body size. Here we have elucidated the BMP transcriptional network and identified cuticle collagen genes as downstream effectors of body size regulation through the BMP pathway. Collagens play diverse roles in biology; mutations are often associated with rare heritable diseases such as osteogenesis imperfecta and Ehlers-Danlos syndrome. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified.

genetics↗