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DPY-17 and MUA-3 Interact for Connective Tissue-Like Tissue Integrity in Caenorhabditis elegans: A Model for Marfan
Pauline Fotopoulos1, Jeongho Kim2, Moonjung Hyun1
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
Abstract:
mua-3 is a Caenorhabditis elegans homolog of the mammalian fibrillin1, a monogenic cause of Marfan syndrome. We identified a new mutation of mua-3 that carries an in-frame deletion of 131 amino acids in the extracellular domain, which allows the mutants to survive in a temperature-dependent manner; at the permissive temperature, the mutants grow normally without obvious phenotypes, but at the nonpermissive temperature, more than 90% die during the L4 molt due to internal organ detachment. Using the temperature-sensitive lethality, we performed unbiased genetic screens to isolate suppressors to find genetic interactors of MUA-3. From two independent screens, we isolated mutations in dpy-17 as a suppressor. RNAi of dpy-17 in mua-3 rescued the lethality, confirming dpy-17 is a suppressor. dpy-17 encodes a collagen known to genetically interact with dpy-31, a BMP-1/Tolloid-like metalloprotease required for TGFβ activation in mammals. Human fibrillin1 mutants fail to sequester TGFβ2 leading to excess TGFβ signaling, which in turn contributes to Marfan syndrome or Marfan-related syndrome. Consistent with that, RNAi of dbl-1, a TGFβ homolog, modestly rescued the lethality of mua-3 mutants, suggesting a potentially conserved interaction between MUA-3 and a TGFβ pathway in C. elegans. Our work provides genetic evidence of the interaction between TGFβ and a fibrillin homolog, and thus provides a simple yet powerful genetic model to study TGFβ function in development of Marfan pathology.
Insights
Researchers identified a temperature-sensitive mutation in mua-3, a gene related to Marfan syndrome. Suppressor screens revealed interactions with dpy-17 and TGFβ signaling, offering a model for Marfan pathology.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- MUA-3 is the Caenorhabditis elegans homolog of mammalian fibrillin1, a key protein implicated in Marfan syndrome.
- Mutations in fibrillin1 can lead to Marfan syndrome by disrupting TGFβ signaling.
- Understanding the genetic interactions of fibrillin homologs is crucial for deciphering Marfan syndrome pathogenesis.
Purpose of the Study:
- To identify genetic interactors of MUA-3 using a temperature-sensitive mutant.
- To investigate the role of MUA-3 in developmental processes and its relationship with TGFβ signaling.
- To establish a genetic model in C. elegans for studying Marfan syndrome.
Main Methods:
- Generated a temperature-sensitive mua-3 mutant with an in-frame deletion.
- Performed unbiased genetic screens to isolate suppressor mutations.
- Utilized RNA interference (RNAi) for gene knockdown and rescue experiments.
- Analyzed genetic interactions with dpy-17 and dbl-1 (a TGFβ homolog).
Main Results:
- A temperature-sensitive mua-3 mutant exhibited lethality at the nonpermissive temperature due to internal organ detachment.
- Mutations in dpy-17 were identified as suppressors of mua-3 lethality, confirmed by RNAi rescue.
- RNAi knockdown of dbl-1 (a TGFβ homolog) partially rescued the mua-3 mutant lethality.
- dpy-17 encodes a collagen, suggesting a link between collagen and TGFβ pathway regulation.
Conclusions:
- This study provides genetic evidence for the interaction between a fibrillin homolog (MUA-3) and the TGFβ signaling pathway in C. elegans.
- The identified genetic interactions, particularly with dpy-17 and dbl-1, highlight conserved mechanisms relevant to Marfan syndrome.
- The temperature-sensitive mua-3 mutant serves as a valuable genetic model for further investigation into TGFβ function and Marfan pathology development.
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