A first-takes-all model of centriole copy number control based on cartwheel elongation

Abstract

How cells control the numbers of its subcellular components is a fundamental question in biology. Given that biosynthetic processes are fundamentally stochastic it is utterly puzzling that some structures display no copy number variation within a cell population. Centriole biogenesis, with each centriole being duplicated once and only once per cell cycle, stands out due to its remarkable fidelity. This is a highly controlled process, which depends on low-abundance rate-limiting factors. How can exactly one centriole copy be produced given the variation in the concentration of these key factors? Hitherto, tentative explanations of this control evoked lateral inhibition- or phase separation-like mechanisms emerging from the dynamics of these rate-limiting factors but how strict centriole number is regulated remains unsolved. Here, a novel solution to centriole copy number control is proposed based on the assembly of a centriolar scaffold, the cartwheel. We assume that cartwheel building blocks accumulate around the mother centriole at supercritical concentrations, sufficient to assemble one or more cartwheels. Our key postulate is that once the first cartwheel is formed it continues to elongate by stacking the intermediate building blocks that would otherwise form supernumerary cartwheels. Using stochastic models and simulations, we show that this mechanism may ensure formation of one and only one cartwheel robustly over a wide range of parameter values. By comparison to alternative models, we conclude that the distinctive signatures of this novel mechanism are an increasing assembly time with cartwheel numbers and the translation of stochasticity in building block concentrations into variation in cartwheel numbers or length.

CCDC15 localizes to the centriole inner scaffold and controls centriole length and integrity

“…Modifications of tubulin subunits such as acetylation, detyrosination, and glutamylation may also contribute to the stability of the centriolar microtubules ( Bayless et al, 2012 ; Guichard et al, 2023 ; Wloga et al, 2017 ). In addition to regulation via centriolar microtubules, cartwheel length and centriole copy number have been proposed to vary depending on the levels of the cartwheel building block Sas-6, which was also shown to regulate centriole length and integrity in mouse embryonic stem cells ( Dias Louro et al, 2021 ; Grzonka and Bazzi, 2022 , Preprint ). Another emerging mechanism that promotes proper centriole length is the initiation and timing of centriole biogenesis by the oscillations of PLK4 at the base of the growing centrioles ( Aydogan et al, 2018 , 2020 ).…”