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Genetic interaction of mammalian IFT-A paralogs regulates cilia disassembly, ciliary entry of membrane protein, Hedgehog signaling and embryogenesis
- Source :
- FASEB J
- Publication Year :
- 2020
-
Abstract
- Primary cilia are sensory organelles that are essential for eukaryotic development and health. These antenna-like structures are synthesized by intraflagellar transport protein complexes, IFT-B and IFT-A, which mediate bi-directional protein trafficking along the ciliary axoneme. Here using mouse embryonic fibroblasts (MEF), we investigate the ciliary roles of two mammalian orthologues of Chlamydomonas IFT-A gene, IFT139, namely Thm1 (also known as Ttc21b) and Thm2 (Ttc21a). Thm1 loss causes perinatal lethality, and Thm2 loss allows survival into adulthood. At E14.5, the number of Thm1;Thm2 double mutant embryos is lower than that for a Mendelian ratio, indicating deletion of Thm1 and Thm2 causes mid-gestational lethality. We examined the ciliary phenotypes of mutant MEF. Thm1-mutant MEF show decreased cilia assembly, increased cilia disassembly, shortened primary cilia, a retrograde IFT defect for IFT and BBS proteins, and reduced ciliary entry of membrane-associated proteins. Thm1-mutant cilia also show a retrograde transport defect for the Hedgehog transducer, Smoothened, and an impaired response to Smoothened agonist, SAG. Thm2-null MEF show normal ciliary dynamics and Hedgehog signaling, but additional loss of a Thm1 allele impairs response to SAG. Further, Thm1;Thm2 double mutant MEF show enhanced cilia disassembly, and increased impairment of INPP5E ciliary import. Thus, Thm1 and Thm2 have unique and redundant roles in MEF. Thm1 regulates cilia assembly, and alone and together with Thm2, regulates cilia disassembly, ciliary entry of membrane-associated protein, Hedgehog signaling, and embryogenesis. These findings shed light on mechanisms underlying Thm1-, Thm2- or IFT-A-mediated ciliopathies.
- Subjects :
- 0301 basic medicine
Male
Mutant
Embryonic Development
Biology
Biochemistry
Article
03 medical and health sciences
Mice
0302 clinical medicine
Intraflagellar transport
INPP5E
Genetics
Animals
Hedgehog Proteins
Cilia
Molecular Biology
Hedgehog
Adaptor Proteins, Signal Transducing
Mice, Knockout
Cilium
Membrane Proteins
Hedgehog signaling pathway
Cell biology
Mice, Inbred C57BL
Protein Transport
030104 developmental biology
Membrane protein
Flagella
sense organs
Smoothened
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- FASEB J
- Accession number :
- edsair.doi.dedup.....576fd9ad072b47129de7a726b535d711