Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis
Adrian Santos-Ledo1,2, Marina Garcia-Macia3,4, Philip D Campbell1
1Department of Developmental and Molecular Biology. Albert Einstein College of Medicine, Bronx, New York, United States of America.
Plos Genetics
|July 18, 2017
Summary
Zebrafish Kif5B kinesin is crucial for cartilage remodeling and chondrocyte maintenance during craniofacial development, functioning distinctly from planar cell polarity pathways. Loss of Kif5B disrupts lysosomal function and leads to chondrocyte death, impacting bone formation.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Skeletal morphogenesis involves diverse mechanisms for bone formation, particularly in species like zebrafish where cartilage templates persist.
- While planar cell polarity (PCP) mediates cartilage remodeling for element lengthening, the mechanisms maintaining the chondrocyte template for ossification are less understood.
Purpose of the Study:
- To investigate the role of kinesin-I genes, specifically Kif5B, in zebrafish craniofacial cartilage remodeling and chondrocyte maintenance.
- To elucidate the molecular mechanisms by which Kif5B influences chondrocyte survival and matrix organization during ossification.
Main Methods:
- CRISPR/Cas9 mutagenesis to generate kif5Blof double mutants in zebrafish.
- Analysis of mutant phenotypes including cell apoptosis, lysosomal function, autophagy markers, and matrix secretion.
- Ultrastructural analysis, transplantation experiments, and chimeric/mosaic analyses to assess cell-autonomous functions and rescue experiments.
Main Results:
- Zygotic Kif5Bs are essential for cartilage remodeling and maintenance in craniofacial development via a PCP-independent mechanism.
- kif5Blof mutants exhibit disrupted lysosomal function, impaired matrix secretion, deregulated autophagy, and chondrocyte apoptosis.
- Kif5B functions cell-autonomously in chondrocyte secretion, nuclear positioning, cell elongation, and hypertrophic chondrocyte maintenance, with mosaic expression of kif5Ba rescuing the phenotype.
Conclusions:
- Kif5B plays an essential, cell-autonomous role in promoting cartilage remodeling and chondrocyte maintenance during zebrafish craniofacial morphogenesis.
- Disruption of Kif5B function leads to chondrocyte death and impaired ossification, highlighting its importance beyond muscle integrity.
- The findings reveal a novel, PCP-distinct mechanism involving Kif5B in regulating chondrocyte biology and skeletal development.
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