DPY-17 and MUA-3 interact for connective tissue-like tissue integrity in Caenorhabditis elegans: A model for Marfan syndrome

Pauline Fotopoulos, Jeongho Kim, Moonjung Hyun, Waiss Qamari, Inhwan Lee, Young Jai You

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
JournalG3: Genes, Genomes, Genetics
Volume5
Issue number7
DOIs
StatePublished - 2015

Keywords

  • Connective tissue
  • Fibrillin-1
  • Marfan syndrome
  • Molting
  • Mua-3

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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