Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network

Abstract

Symmetry breaking, a central principle of physics, has been hailed as the driver of selforganization in biological systems in general and biogenesis of cellular organelles in particular, but the molecular mechanisms of symmetry breaking only begin to become understood. Centrioles, the structural cores of centrosomes and cilia, must duplicate every cell cycle to ensure their faithful inheritance through cellular divisions. Work in model organisms identified conserved proteins required for centriole duplication and found that altering their abundance affects centriole number. However, the biophysical principles that ensure that, under physiological conditions, only a single procentriole is produced on each mother centriole remain enigmatic. Here we propose a mechanistic biophysical model for the initiation of procentriole formation in mammalian cells. We posit that interactions between the master regulatory kinase PLK4 and its activator-substrate STIL form the basis of the procentriole initiation network. The model faithfully recapitulates the experimentally observed transition from PLK4 uniformly distributed around the mother centriole, the "ring", to a unique PLK4 focus, the "spot", that triggers the assembly of a new procentriole. This symmetry breaking requires a dual positive feedback based on autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4-STIL complexes by phosphorylated STIL. We find that, contrary to previous proposals, in situ degradation of active PLK4 is insufficient to break symmetry. Instead, the model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes explains both the instability of the PLK4 ring and formation of the unique PLK4 spot. In the model, strong competition at physiologically normal parameters robustly produces a single procentriole, while increasing overexpression of PLK4 and STIL weakens the competition and causes progressive addition of procentrioles in agreement with experimental observations.

A free-running oscillator times and executes centriole biogenesis

“…Polo-like kinase 4 (Plk4) is the master regulator of centriole biogenesis, and it is initially recruited to a ring around the mother centriole, but this ring ultimately resolves into a single focus on the side of the mother, defining the site of daughter centriole assembly (Banterle and Gönczy, 2017;Fırat-Karalar and Stearns, 2014;Leda et al, 2018;Nigg and Holland, 2018;Ohta et al, 2018). Unexpectedly, we found that Plk4 not only determines the position of this site, but also helps to establish the inverse relationship between the rate and period of daughter centriole growth .…”

Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors

“…Accumulation of centriole duplication players at the daughter centriole during A-phase, together with the observed association of deuterosomes with the proximal part of the daughter centriole 8 , suggests that, similar to cycling cells, a centriolar wall may serve as a preferential but dispensable nucleation site ensuring a structural patterning 19 and/or facilitating nucleation events 25,26 . Whether the structure of centrioles is affected by the absence of parental centriole needs further investigation 19 .…”

Massive centriole production can occur in the absence of deuterosomes in multiciliated cells

“…4c and Supplementary Videos 4,5). This non-homogenous distribution may arise as a result of a symmetry-breaking reaction that creates a non-uniform distribution of PLK4, similar to what occurs in cycling cells 27 . Alternatively, procentrioles may detach from the walls of the parent centrioles, which could explain their presence in close proximity to the parent centrioles (Fig.…”