Mutagenesis and Imaging Studies of BMP Signaling Mechanisms in C. elegans

Savage-Dunn, Cathy; Gleason, Ryan J; Li, Jun; Padgett, Richard W.

doi:10.1007/978-1-4939-8904-1_6

Cited by 7 publications

(9 citation statements)

References 50 publications

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“…The microscope conditions were optimized with respect to the control and test conditions and kept consistent within each trial. Mean fluorescence intensities were measured as previously described using the Zeiss ZEN lite software 39 .…”

Section: Imagingmentioning

confidence: 99%

“…To address this question, we challenged wild-type or dbl-1(-) animals expressing an integrated fluorescent DBL-1 pathway reporter to these bacteria and analyzing reporter fluorescence in L2 hypodermal nuclei. The expression of this reporter is robust in hypodermal nuclei at the L2 stage, and changes in DBL-1 affect hypodermal expression of RAD-SMAD 39 . This reporter (called RAD-SMAD) consists of the GFP gene under the control of multiple copies of a Smad binding element sequence 50 .…”

Section: Dbl-1 Signaling Is Activated In Response To Gram-negative Bacteria and Is Repressed In Response To Gram-positive Bacteriamentioning

confidence: 99%

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The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses inC. elegans

Madhu

Hanson

Gumienny

2021

Preprint

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Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

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Section: Imagingmentioning

confidence: 99%

Section: Dbl-1 Signaling Is Activated In Response To Gram-negative Bacteria and Is Repressed In Response To Gram-positive Bacteriamentioning

confidence: 99%

The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses inC. elegans

Madhu

Hanson

Gumienny

2021

Preprint

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“…In particular, reduced BMP signaling leads to a small body size phenotype, while increased BMP signaling makes C. elegans worms longer. Furthermore, altered BMP signaling can suppress the postembryonic mesoderm patterning defect caused by mutations in sma-9, which encodes a Zn finger-containing transcription factor (16,17) (SI Appendix, Fig. S1B).…”

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confidence: 99%

Tetraspanins TSP-12 and TSP-14 function redundantly to regulate the trafficking of the type II BMP receptor in Caenorhabditis elegans

Liu

Shi

Nzessi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Tetraspanins are a unique family of 4-pass transmembrane proteins that play important roles in a variety of cell biological processes. We have previously shown that 2 paralogous tetraspanins in Caenorhabditis elegans, TSP-12 and TSP-14, function redundantly to promote bone morphogenetic protein (BMP) signaling. The underlying molecular mechanisms, however, are not fully understood. In this study, we examined the expression and subcellular localization patterns of endogenously tagged TSP-12 and TSP-14 proteins. We found that TSP-12 and TSP-14 share overlapping expression patterns in multiple cell types, and that both proteins are localized on the cell surface and in various types of endosomes, including early, late, and recycling endosomes. Animals lacking both TSP-12 and TSP-14 exhibit reduced cell-surface levels of the BMP type II receptor DAF-4/BMPRII, along with impaired endosome morphology and mislocalization of DAF-4/BMPRII to late endosomes and lysosomes. These findings indicate that TSP-12 and TSP-14 are required for the recycling of DAF-4/BMPRII. Together with previous findings that the type I receptor SMA-6 is recycled via the retromer complex, our work demonstrates the involvement of distinct recycling pathways for the type I and type II BMP receptors and highlights the importance of tetraspanin-mediated intracellular trafficking in the regulation of BMP signaling in vivo. As TSP-12 and TSP-14 are conserved in mammals, our findings suggest that the mammalian TSP-12 and TSP-14 homologs may also function in regulating transmembrane protein recycling and BMP signaling.

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“…Specifically, tsp-12(0); tsp-14(0) double null mutants exhibit maternal-effect embryonic lethality (Emb) and are egg-laying defective (Egl) due to defects in vulva development, two processes known to be regulated by Notch signaling [13]. tsp-12(0); tsp-14(0) double null mutants are also small and exhibit a suppression of the sma-9(0) postembryonic mesoderm defect (Susm), processes regulated by BMP signaling [17,29]. Like TSP-14, TSP-12 is localized to various endosomes, as well as on the basolateral membrane of polarized vulval and intestinal epithelial cells [16].…”

Section: Discussionmentioning

confidence: 99%

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

2022

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Tetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in metazoans. While much is known about their biochemical properties, the in vivo functions and distribution patterns of different tetraspanin proteins are less understood. Previous studies have shown that two paralogous tetraspanins that belong to the TspanC8 subfamily, TSP-12 and TSP-14, function redundantly to promote both Notch signaling and bone morphogenetic protein (BMP) signaling in C. elegans. TSP-14 has two isoforms, TSP-14A and TSP-14B, where TSP-14B has an additional 24 amino acids at its N-terminus compared to TSP-14A. By generating isoform specific knock-ins and knock-outs using CRISPR, we found that TSP-14A and TSP-14B share distinct as well as overlapping expression patterns and functions. While TSP-14A functions redundantly with TSP-12 to regulate body size and embryonic and vulva development, TSP-14B primarily functions redundantly with TSP-12 to regulate postembryonic mesoderm development. Importantly, TSP-14A and TSP-14B exhibit distinct subcellular localization patterns. TSP-14A is localized apically and on early and late endosomes. TSP-14B is localized to the basolateral cell membrane. We further identified a di-leucine motif within the N-terminal 24 amino acids of TSP-14B that serves as a basolateral membrane targeting sequence, and showed that the basolateral membrane localization of TSP-14B is important for its function. Our work highlights the diverse and intricate functions of TspanC8 tetraspanins in C. elegans, and demonstrates the importance of dissecting the functions of these important proteins in an intact living organism.

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Mutagenesis and Imaging Studies of BMP Signaling Mechanisms in C. elegans

Cited by 7 publications

References 50 publications

The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses inC. elegans

The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses inC. elegans

Tetraspanins TSP-12 and TSP-14 function redundantly to regulate the trafficking of the type II BMP receptor in Caenorhabditis elegans

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

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