DPY-17 and MUA-3 Interact for Connective Tissue-Like Tissue Integrity in Caenorhabditis elegans: A Model for Marfan Syndrome.
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.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
Pauline
P
Fotopoulos
Department of Biological Sciences, Inha University, Incheon, 402-751, South Korea.
Jeongho
J
Kim
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
Moonjung
M
Hyun
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
Waiss
W
Qamari
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
Inhwan
I
Lee
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298 yjyou@vcu.edu.
Young-Jai
http://orcid.org/0000-0002-5716-5418
YJ
You
D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism*; D004195:Disease Models, Animal; D005804:Genes, Lethal; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics / Q000473:pathology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D024041:Non-Fibrillar Collagens / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D015398:Signal Transduction; D013696:Temperature; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; C117509:Dbl-1 protein, C elegans; C432914:MUA-3 protein, C elegans; D009479:Neuropeptides; D024041:Non-Fibrillar Collagens; D016212:Transforming Growth Factor beta; C116307:dpy-17 protein, C elegans
Fibrillin-1; Marfan syndrome; connective tissue; molting; mua-3