Emerging roles of centrosome cohesion

Abstract

The centrosome, consisting of centrioles and the associated pericentriolar material, is the main microtubule-organizing centre (MTOC) in animal cells. During most of interphase, the two centrosomes of a cell are joined together by centrosome cohesion into one MTOC. The most dominant element of centrosome cohesion is the centrosome linker, an interdigitating, fibrous network formed by the protein C-Nap1 anchoring a number of coiled-coil proteins including rootletin to the proximal end of centrioles. Alternatively, centrosomes can be kept together by the action of the minus end directed kinesin motor protein KIFC3 that works on interdigitating microtubules organized by both centrosomes and probably by the actin network. Although cells connect the two interphase centrosomes by several mechanisms into one MTOC, the general importance of centrosome cohesion, particularly for an organism, is still largely unclear. In this article, we review the functions of the centrosome linker and discuss how centrosome cohesion defects can lead to diseases.

Keywords: centrosome cohesion; centrosome linker; centrosomes.

Figure 1.

The centrosome linker and MT-based centrosome cohesion. (a) Molecular composition of the centrosome linker in interphase. C-Nap1 docks to the proximal end of the centrioles forming a ring-like structure that anchors centrosome linker proteins such as CEP68 and rootletin. Rootletin and CEP68 form the interwoven filaments of the centrosome linker. Abbreviations: DAs, distal appendages; SDAs, subdistal appendages [32]. (b) An overview of centrosome linker assembly. The centrosome linker protein C-Nap1 anchors rootletin filaments to the proximal end of centrioles. CEP68 interacts and stabilizes the rootletin fibre [32,146]. (c) An overview of centrosome linker disassembly and centrosome separation. Disassembly of centrosome linker allows centrosome separation. The separated centrosomes migrate to form the opposite poles of the bipolar spindle. MTs, microtubules. (d) MT-based centrosome cohesion in interphase. KIFC3 cross-links MTs organized by SDAs of the mother and PCM of the daughter centrosomes, thus creating pulling forces that keep the centrosomes together during interphase [20].

Figure 2.

Genes involved in centrosome cohesion affect brain development. CDK5RAP2/CEP215 or NIN mutations possibly lead to aberrant centrosome cohesion, resulting in dysregulated spindle orientation and asymmetric centrosome inheritance, triggering premature differentiation of the neural stem cells, which eventually results in loss of stem cells and reduced brain size [–90].

Figure 3.

Centrosome cohesion in testis development. Cep250 KO mice, which lack the centrosome linker, show defects in centrosome cohesion and premature centrosome separation in interphase-early mitosis. As a result, timely establishment of E-cadherin polarity pattern in early mitosis was disturbed, leading to dysregulation of spindle orientation and asymmetric centrosome inheritance. Centrosome cohesion defects consequently cause loss of the stem cell population and germ cell apoptosis [95].

Figure 4.

Diseases and disorders associated with centrosome cohesion defects. The diagram summarizes diseases (pink panels) and disorders (grey panels) associated with alterations of genes encoding known centrosome cohesion proteins (green panels) [–,,,,,,,–126,131,133,147].