title: Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4.
abstract: Primary cilia are assembled and maintained by evolutionarily conserved intraflagellar transport (IFT) proteins that are involved in the coordinated movement of macromolecular cargo from the basal body to the cilium tip and back. The IFT machinery is organized in two structural complexes named complex A and complex B. Recently, inactivation in the mouse germline of Ift genes belonging to complex B revealed a requirement of ciliogenesis, or proteins involved in ciliogenesis, for Sonic Hedgehog (Shh) signaling in mammals. Here we report on a complex A mutant mouse, defective for the Ift122 gene. Ift122-null embryos show multiple developmental defects (exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development) that result in lethality. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively. Impairment of the Shh pathway was apparent in both neural tube patterning (expansion of motoneurons and rostro-caudal level-dependent contraction or expansion of the dorso-lateral interneurons), and limb patterning (ectrosyndactyly). These phenotypes are distinct from both complex B IFT mutant embryos and embryos defective for the ciliary protein hennin/Arl13b, and suggest reduced levels of both Gli2/Gli3 activator and Gli3 repressor functions. We conclude that complex A and complex B factors play similar but distinct roles in ciliogenesis and Shh/Gli3 signaling.
authors.affiliation: Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cortellino
authors.forename: Chengbing
authors.initials: C
authors.lastname: Wang
authors.forename: Baolin
authors.initials: B
authors.lastname: Wang
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Bassi
authors.forename: Elena
authors.initials: E
authors.lastname: Caretti
authors.forename: Delphine
authors.initials: D
authors.lastname: Champeval
authors.forename: Amelie
authors.initials: A
authors.lastname: Calmont
authors.forename: Michal
authors.initials: M
authors.lastname: Jarnik
authors.forename: John
authors.initials: J
authors.lastname: Burch
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zaret
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D019521:Body Patterning; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D004260:DNA Repair; D020964:Embryo Loss / Q000235:genetics*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D047108:Embryonic Development; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism*; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; C534510:Ift122 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D004706:Endodeoxyribonucleases; C492249:Mbd4 protein, mouse