Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis.
2007
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 (μCT) 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.
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