A theory of centriole duplication based on self-organized spatial pattern formation

Abstract

In each cell cycle, centrioles are duplicated to produce a single copy of each preexisting centriole. At the onset of centriole duplication, the master regulator Polo-like kinase 4 (Plk4) undergoes a dynamic change in its spatial pattern around the preexisting centriole, forming a single duplication site. However, the significance and mechanisms of this pattern transition remain unknown. Using super-resolution imaging, we found that centriolar Plk4 exhibits periodic discrete patterns resembling pearl necklaces, frequently with single prominent foci. Mathematical modeling and simulations incorporating the self-organization properties of Plk4 successfully generated the experimentally observed patterns. We therefore propose that the self-patterning of Plk4 is crucial for the regulation of centriole duplication. These results, defining the mechanisms of self-organized regulation, provide a fundamental principle for understanding centriole duplication.

A self-assembled cylindrical platform for Plk4-induced centriole biogenesis

“…In line with this notion, mutations on the hydrophobic residues present in their respective motifs greatly impair the ability of Cep63 and Cep152 to generate a spherical assembly both in vitro and in vivo [70]. While these findings hint that the Cep63-Cep152 complex possesses an intrinsic physico-chemical ability to generate a self-assembly, the formation of a spherical assembly is somewhat unanticipated, given its cylinder-like localization pattern around a centriole [47][48][49]. Surprisingly, however, the Cep63-Cep152 complex efficiently generates a cylindrical selfassembly when placed on a two-dimensional surface [32] (figure 3a, left).…”

“…As Cep152 ( presumably as a dimeric Cep63-Cep152 complex or trimeric Cep57-Cep63-Cep152) is recruited, Cep152 snatches Plk4 away from the Cep192 scaffold (the inset diagrams) and assembles around the Cep192 layer in late G1, prompting the repositioning of Plk4 to the outer edge of the Cep152 scaffold. Note that because Cep57, Cep152 and inactivated Plk4 show a localization pattern of a ninefold radial symmetry [48,49], the Cep63-Cep152 assemblies are depicted in clusters.…”

“…ring-state Plk4) may stochastically cross a critical point of phosphorylating the CPB, thus causing the enzyme to undergo LLPS, generating patches of Plk4 condensates [38]. Based on the data obtained with the N-terminal fragment of Plk4 [37], catalytically inactive Plk4 (indicated by a black dimer) may also possess the LLPS capacity (circular arrow, first panel), which may help active Plk4 to generate condensates through a lateral inhibition self-patterning process [37,49]. A single Plk4 focus (i.e.…”

“…A single Plk4 focus (i.e. dot-state Plk4) is thought to ultimately emerge from subsequent amplification and competition processes [49,75]. Condensed active (red, shown in cluster), but not partially active (dark burgundy), Plk4 could evade βTrCP-mediated suicidal degradation [38].…”

Plk4 triggers autonomous de novo centriole biogenesis and maturation

“…The change in the kinetics of de novo centriole assembly in response to Plk4 concentration allied to the current body of knowledge in the centrosome field, collectively suggest that centriole formation is critically regulated by timely concentration of centrosomal molecules in one single place (Rale et al, 2018; Takao et al, 2019). But what initiates the concentration of these centrosomal molecules?…”