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

Dev Biol. 2009 Jan 1;325(1):225-37. doi: 10.1016/j.ydbio.2008.10.020. Epub 2008 Oct 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alleles
  • Animals
  • Body Patterning
  • Cilia / metabolism*
  • Cilia / ultrastructure
  • Cytoskeletal Proteins
  • DNA Repair*
  • Embryo Loss / genetics*
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / ultrastructure
  • Embryonic Development
  • Endodeoxyribonucleases / genetics*
  • Endodeoxyribonucleases / metabolism
  • Extremities / embryology
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Gene Silencing*
  • Hedgehog Proteins / metabolism*
  • Homozygote
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Neurons / cytology
  • Neurons / metabolism
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Hedgehog Proteins
  • Ift122 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Endodeoxyribonucleases
  • Mbd4 protein, mouse