title: Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis.
abstract: The motor protein Kif3a and primary cilia regulate important developmental processes, but their roles in skeletogenesis remain ill-defined. Here we created mice deficient in Kif3a in cartilage and focused on the cranial base and synchondroses. Kif3a deficiency caused cranial base growth retardation and dysmorphogenesis, which were evident in neonatal animals by anatomical and micro-computed tomography (microCT) inspection. Kif3a deficiency also changed synchondrosis growth plate organization and function, and the severity of these changes increased over time. By postnatal day (P)7, mutant growth plates lacked typical zones of chondrocyte proliferation and hypertrophy, and were instead composed of chondrocytes with an unusual phenotype characterized by strong collagen II (Col2a1) gene expression but barely detectable expression of Indian hedgehog (Ihh), collagen X (Col10a1), Vegf (Vegfa), MMP-13 (Mmp13) and osterix (Sp7). Concurrently, unexpected developmental events occurred in perichondrial tissues, including excessive intramembranous ossification all along the perichondrial border and the formation of ectopic cartilage masses. Looking for possible culprits for these latter processes, we analyzed hedgehog signalling topography and intensity by monitoring the expression of the hedgehog effectors Patched 1 and Gli1, and of the hedgehog-binding cell-surface component syndecan 3. Compared with controls, hedgehog signaling was quite feeble within mutant growth plates as early as P0, but was actually higher and was widespread all along mutant perichondrial tissues. Lastly, we studied postnatal mice deficient in Ihh in cartilage; their cranial base defects only minimally resembled those in Kif3a-deficient mice. In summary, Kif3a and primary cilia make unique contributions to cranial base development and synchondrosis growth plate function. Their deficiency causes abnormal topography of hedgehog signaling, growth plate dysfunction, and un-physiologic responses and processes in perichondrial tissues, including ectopic cartilage formation and excessive intramembranous ossification.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, PA 19107, USA. eiki.koyama@jefferson.edu
authors.forename: Eiki
authors.initials: E
authors.lastname: Koyama
authors.forename: Blanche
authors.initials: B
authors.lastname: Young
authors.forename: Motohiko
authors.initials: M
authors.lastname: Nagayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibukawa
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Maeda
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Buer
authors.initials: B
authors.lastname: Song
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pacifici
mesh_terms: D000818:Animals; D002356:Cartilage / Q000196:embryology* / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism / Q000503:physiopathology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D016547:Kinesins / Q000172:deficiency*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012886:Skull / Q000196:embryology*; D053670:Syndecan-3 / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C508302:Sdc3 protein, mouse; D053670:Syndecan-3; D000071676:Zinc Finger Protein GLI1; D016547:Kinesins