K-Ras controls asymmetric cell divisions from the primary cilium

Chippalkatti, R.; Schaffner-Reckinger, E.; Gaigneaux, A.; Parisi, B.; Bottone, S.; Laurini, C.; Rouzbahani, Y.; Dijkers, M.; Gomez-Mulas, A.; Sauter, T.; den Hertog, J.; Eggeling, C.; Abankwa, D. K.

doi:10.64898/2026.03.05.709789

bioRxiv · 10.64898/2026.03.05.709789

K-Ras controls asymmetric cell divisions from the primary cilium

Chippalkatti, R.·Schaffner-Reckinger, E.·Gaigneaux, A.·Parisi, B.·Bottone, S.·Laurini, C.·Rouzbahani, Y.·Dijkers, M.·Gomez-Mulas, A.·Sauter, T.·den Hertog, J.·Eggeling, C.·Abankwa, D. K.

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Abstract

The Ras-MAPK pathway drives central cellular processes, including cell proliferation and differentiation. How exactly Ras controls differentiation is however not understood. Supported by mathematical modelling and single-cell RNA sequencing we show that K-Ras4B sustains ciliation during differentiation thus restricting commitment of skeletal muscle stem and progenitor cells during asymmetric cell divisions. Modulation of K-Ras4B abundance or expression of oncogenic K-Ras4B-G12C perturb normal differentiation. K-Ras4B, but not N-Ras and H-Ras, localizes to the primary cilium and its abundance there depends on the ciliary trafficking chaperone PDE6D. The presence of B-Raf and active MEK at the base of and active ERK inside the cilium suggests that K-Ras4B is active there. Conditions that localize a K-Ras4B mutant only to the cilium are sufficient to sustain ciliation and normal differentiation. Finally, in vivo modulation of K-Ras4B activity during zebrafish embryogenesis perturbs ciliation-dependent heart-looping. Our results thus imply a novel fundamental role of K-Ras4B in controlling ciliation and differentiation and suggest an explanation for the phenotypic similarities between RASopathies and ciliopathies.

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Chippalkatti, R., Schaffner-Reckinger, E., Gaigneaux, A., Parisi, B., Bottone, S., Laurini, C., Rouzbahani, Y., Dijkers, M., Gomez-Mulas, A., Sauter, T., den Hertog, J., Eggeling, C., Abankwa, D. K.. 2026-03-06. K-Ras controls asymmetric cell divisions from the primary cilium. https://doi.org/10.64898/2026.03.05.709789

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