KIF5B modulates central spindle organization in late-stage cytokinesis in chondrocytes

Abstract

Background The growth plate is a special region of the cartilage that drives longitudinal growth of long bones. Proliferating chondrocytes in the growth plate, arranged in columns, divide perpendicular to the long axis of the growth plate then intercalate to re-align with parental columns. Which molecular partners maintain growth plate columnar structures and chondrocyte cytokinesis has not been fully revealed. It is reported that kinesin family member 3A (KIF3A), a subunit of kinesin-2, plays an important role in maintaining columnar organization in growth plates via controlling primary cilia formation and cell proliferation. Result Here we identify kinesin family member 5B (KIF5B), the heavy chain of kinesin-1, a ubiquitously expressed motor protein for anterograde intracellular transport along the microtubule network, as a key modulator of cytokinesis in chondrocytes via maintenance of central spindle organization. We show that KIF5B is concentrated in the central spindle during cytokinesis in both primary chondrocytes and chondrogenic ATDC5 cells. Conclusion The failure of cytokinesis in KIF5B null chondrocytes leads to incomplete cell rotation, disrupting proliferation and differentiation, and results in a disorganized growth plate.

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

“…Two animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte‐specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity 16 . Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages 17 .…”

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

“…Mutations could cause reduced proliferation of growth plate chondrocytes, which in turn could limit bone growth. Disrupting cytokinesis in the growth plate causes shorter bones and stature in mice ( Gan et al, 2019 ), and mutations in KIF22 could affect development via this mechanism. The presence of pathologies in other cartilaginous tissues, including the larynx and trachea, in patients with mutations in the motor domain of KIF22 ( Boyden et al, 2011 ) is also consistent with a disease etiology based in aberrant chondrocyte proliferation.…”

Role of Primary Cilia in Bone and Cartilage

“…Similar to KIF3A and KIF7, deletion of KIF5B in chondrocytes impairs chondrocyte proliferation and differentiation. Notably, loss of KIF5B in chondrocytes leads to delayed and defective cytokinesis, which thereby causes incomplete cell rotation, disrupts proliferation and differentiation, and results in a disorganized growth plate (Gan et al 2019). These findings demonstrate that KIF5B is a key modulator of cytokinesis in chondrocytes via maintenance of central spindle organization.…”

“…These findings demonstrate that KIF5B is a key modulator of cytokinesis in chondrocytes via maintenance of central spindle organization. KIF3B and KIF4 have been found to participate in cytokinesis and central spindle assembly (Gan et al 2019). Whether other KIF proteins or IFT proteins also play role(s) in regulating cytokinesis needs to be further studied.…”