Document Detail


Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation.
MedLine Citation:
PMID:  21945076     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tumor necrosis factor alpha receptor 3 interacting protein 1 (Traf3ip1), also known as MIPT3, was initially characterized through its interactions with tubulin, actin, TNFR-associated factor-3 (Traf3), IL-13R1, and DISC1. It functions as an inhibitor of IL-13-mediated phosphorylation of Stat6 and in sequestration of Traf3 and DISC1 to the cytoskeleton. Studies of the Traf3ip1 homologs in C. elegans (DYF-11), Zebrafish (elipsa), and Chlamydomonas (IFT54) revealed that the protein localizes to the cilium and is required for ciliogenesis. Similar localization data has now been reported for mammalian Traf3ip1. This raises the possibility that Traf3ip1 has an evolutionarily conserved role in mammalian ciliogenesis in addition to its previously indicated functions. To evaluate this possibility, a Traf3ip1 mutant mouse line was generated. Traf3ip1 mutant cells are unable to form cilia. Homozygous Traf3ip1 mutant mice are not viable and have both neural developmental defects and polydactyly, phenotypes typical of mouse mutants with ciliary assembly defects. Furthermore, in Traf3ip1 mutants the hedgehog pathway is disrupted, as evidenced by abnormal dorsal-ventral neural tube patterning and diminished expression of a hedgehog reporter. Analysis of the canonical Wnt pathway indicates that it was largely unaffected; however, specific domains in the pharyngeal arches have elevated levels of reporter activity. Interestingly, Traf3ip1 mutant embryos and cells failed to show alterations in IL-13 signaling, one of the pathways associated with its initial discovery. Novel phenotypes observed in Traf3ip1 mutant cells include elevated cytosolic levels of acetylated microtubules and a marked increase in cell size in culture. The enlarged Traf3ip1 mutant cell size was associated with elevated basal mTor pathway activity. Taken together, these data demonstrate that Traf3ip1 function is highly conserved in ciliogenesis and is important for proper regulation of a number of essential developmental and cellular pathways. The Traf3ip1 mutant mouse and cell lines will provide valuable resources to assess cilia function in mammalian development and also serve as a tool to explore the potential connections between cilia and cytoskeletal dynamics, mTor regulation, and cell volume control.
Authors:
Nicolas F Berbari; Nicholas W Kin; Neeraj Sharma; Edward J Michaud; Robert A Kesterson; Bradley K Yoder
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-16
Journal Detail:
Title:  Developmental biology     Volume:  360     ISSN:  1095-564X     ISO Abbreviation:  Dev. Biol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-14     Completed Date:  2012-01-05     Revised Date:  2014-11-05    
Medline Journal Info:
Nlm Unique ID:  0372762     Medline TA:  Dev Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  66-76     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics*,  physiology*
Animals
Cell Size*
Cilia / genetics*,  physiology*
Embryonic Development / genetics*,  physiology*
Female
Hedgehog Proteins / metabolism
Interleukin-13 / metabolism
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Microtubule-Associated Proteins / genetics*,  physiology*
Mutation*
Neural Tube / embryology,  metabolism
Pregnancy
Signal Transduction
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / physiology
Grant Support
ID/Acronym/Agency:
F32 AI078662/AI/NIAID NIH HHS; F32 AI078662/AI/NIAID NIH HHS; F32 DK088404/DK/NIDDK NIH HHS; F32 DK088404/DK/NIDDK NIH HHS; P30 DK074038/DK/NIDDK NIH HHS; P30 DK074038/DK/NIDDK NIH HHS; R01 AI014782/AI/NIAID NIH HHS; R01 HD056030/HD/NICHD NIH HHS; R01 HD056030/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Hedgehog Proteins; 0/Interleukin-13; 0/Microtubule-Associated Proteins; 0/TRAF3IP1 protein, mouse; 0/Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Comments/Corrections

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