Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms.
Hedgehog signaling plays an essential role in patterning of the vertebrate skeleton. Here we demonstrate that conditional inactivation of the Kif3a subunit of the kinesin-2 intraflagellar transport motor in mesenchymal skeletal progenitor cells results in severe patterning defects in the craniofacial area, the formation of split sternum and the development of polydactyly. These deformities are reminiscent of those previously described in mice with deregulated hedgehog signaling. We show that in Kif3a-deficient mesenchymal tissues both the repressor function of Gli3 transcription factor and the activation of the Shh transcriptional targets Ptch and Gli1 are compromised. Quantitative analysis of gene expression demonstrates that the Gli1 transcript level is dramatically reduced, whereas Gli3 expression is not significantly affected by kinesin-2 depletion. However, the motor appears to be required for the efficient cleavage of the full-length Gli3 transcription factor into a repressor form.
Kolpakova-Hart
Elona
E
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
Jinnin
Masatoshi
M
Hou
Bo
B
Fukai
Naomi
N
Olsen
Bjorn R
BR
D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning / Q000502:physiology*; D001846:Bone Development; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
C498520:Gli1 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3; D016547:Kinesins
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