Studies in genetically tractable organisms such as the nematode Caenorhabditis elegans have led to pioneering insights into conserved developmental regulatory mechanisms. For example, Smad signal ...transducers for the transforming growth factor beta (TGF‐β) superfamily were first identified in C. elegans and in the fruit fly Drosophila. Recent studies of TGF‐β signaling and the extracellular matrix (ECM) in C. elegans have forged unexpected links between signaling and the ECM, yielding novel insights into the reciprocal interactions that occur across tissues and spatial scales, and potentially providing new opportunities for the study of biomechanical regulation of gene expression.
Key Findings
Studies in C. elegans have provided insight into the mechanisms of TGF‐beta signaling and the functions of FACIT collagens in the extracellular matrix.
Recent advances have identified reciprocal interactions between TGF‐beta signaling and the extracellular matrix.
These studies have implications for the regulation of body size and for mechanical regulation of gene expression.
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 fully understood. 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 additional IIS functions including dauer formation, aging, 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.
The Transforming Growth Factor-β (TGF-β) superfamily of signaling molecules plays critical roles in development, differentiation, homeostasis, and disease. Due to the conservation of these ligands ...and their signaling pathways, genetic studies in invertebrate systems including the nematode
Caenorhabditis elegans
have been instrumental in identifying signaling mechanisms.
C. elegans
is also a premier organism for research in longevity and healthy aging. Here we summarize current knowledge on the roles of TGF-β signaling in aging and immunity.
The Transforming Growth Factor beta (TGF-β) 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 may enhance, repress, or generate novel functions. In the nematode Caenorhabditis elegans , there are only five TGF-β 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-β/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-β ligands play a role in survival on bacterial pathogens. We also demonstrate that multiple TGF-β ligand pairs act nonredundantly 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-β/Activin-like ligand TIG-3 function together. Structural modeling supports the potential for TIG-2 and TIG-3 to form heterodimers. Additionally, we identify TIG-2 and TIG-3 as members of a rare subset of TGF-β ligands lacking the conserved cysteine responsible for disulfide linking mature dimers. 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-β/Activin signaling pathway do not play a major role in survival. These results demonstrate a novel potential for BMP and TGF-β/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.
Numerous conserved signaling pathways play critical roles in aging, including insulin/IGF-1, TGF-β, and Wnt pathways. Some of these pathways also play prominent roles in the formation and maintenance ...of the extracellular matrix. The nematode
has been an enduringly productive system for the identification of conserved mechanisms of biological aging. Recent studies in
highlight the regulatory circuits between conserved signaling pathways and the extracellular matrix, revealing a bidirectional relationship between these factors and providing a platform to address how regulation of and by the extracellular matrix can impact lifespan and organismal health during aging. These discoveries provide new opportunities for clinical advances and novel therapeutic strategies.
Chloride intracellular channel proteins (CLICs) are multi-functional proteins that are expressed in various cell types and differ in their subcellular location. Two CLIC homologs, EXL-1 (excretory ...canal abnormal like-1) and EXC-4 (excretory canal abnormal- 4), are encoded in the Caenorhabditis elegans genome, providing an excellent model to study the functional diversification of CLIC proteins. EXC-4 functions in excretory canal formation during normal animal development. However, to date, the physiological function of EXL-1 remains largely unknown. In this study, we demonstrate that EXL-1 responds specifically to heat stress and translocates from the cytoplasm to the nucleus in intestinal cells and body wall muscle cells under heat shock. In contrast, we do not observe EXC-4 nuclear translocation under heat shock. Full protein sequence analysis shows that EXL-1 bears a non-classic nuclear localization signal (NLS) that EXC-4 is lacking. All mammalian CLIC members have a nuclear localization signal, with the exception of CLIC3. Our phylogenetic analysis of the CLIC gene families across various animal species demonstrates that the duplication of CLICs in protostomes and deuterostomes occurred independently and that the NLS was subsequently lost in amniotes and nematodes, suggesting convergent evolution. We also observe that EXL-1 nuclear translocation occurs in a timely ordered manner in the intestine, from posterior to anterior regions. Finally, we find that exl-1 loss of function mutants are more susceptible to heat stress than wild-type animals, demonstrating functional relevance of the nuclear translocation. This research provides the first link between CLICs and environmental heat stress. We propose that C. elegans CLICs evolved to achieve different physiological functions through subcellular localization change and spatial separation in response to external or internal signals.
Apical extracellular matrices (aECMs) form a physical barrier to the environment. In
, the epidermal aECM, the cuticle, is composed mainly of different types of collagen, associated in ...circumferential ridges separated by furrows. Here, we show that in mutants lacking furrows, the normal intimate connection between the epidermis and the cuticle is lost, specifically at the lateral epidermis, where, in contrast to the dorsal and ventral epidermis, there are no hemidesmosomes. At the ultrastructural level, there is a profound alteration of structures that we term 'meisosomes,' in reference to eisosomes in yeast. We show that meisosomes are composed of stacked parallel folds of the epidermal plasma membrane, alternately filled with cuticle. We propose that just as hemidesmosomes connect the dorsal and ventral epidermis, above the muscles, to the cuticle, meisosomes connect the lateral epidermis to it. Moreover, furrow mutants present marked modifications of the biomechanical properties of their skin and exhibit a constitutive damage response in the epidermis. As meisosomes co-localise to macrodomains enriched in phosphatidylinositol (4,5) bisphosphate, they could conceivably act, like eisosomes, as signalling platforms, to relay tensile information from the aECM to the underlying epidermis, as part of an integrated stress response to damage.
Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode
has emerged as a powerful, ...genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the
homolog of bone morphogenetic protein 2/4 (BMP2/4), 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 in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in
through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.
Abstract
Studies in genetically tractable organisms such as the nematode
Caenorhabditis elegans
have led to pioneering insights into conserved developmental regulatory mechanisms. For example, Smad ...signal transducers for the transforming growth factor beta (TGF‐β) superfamily were first identified in
C. elegans
and in the fruit fly Drosophila. Recent studies of TGF‐β signaling and the extracellular matrix (ECM) in
C. elegans
have forged unexpected links between signaling and the ECM, yielding novel insights into the reciprocal interactions that occur across tissues and spatial scales, and potentially providing new opportunities for the study of biomechanical regulation of gene expression.
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