Centrosome in Cell Division, Development and Disease

Abstract

The centrosome is a non‐membrane‐bound organelle present in most animal cells and it functions as the major microtubule‐organising centre (MTOC). Recent findings have revealed the detailed molecular and structural features of the centrosome, and architectural and functional changes at the centrosome during the cell cycle. The centriole, the organisational heart of the centrosome, duplicates once each cell cycle and depends on a hierarchy of regulatory and assembly factors for its biogenesis. The centrosome plays important roles in dividing and nondividing cells. This importance is reflected in the appearance of several human developmental disorders when genes encoding centrosomal proteins are mutated. The centriole is essential for the formation of cilia, the cell's ‘antennae’ that receive and transmit signals and sensory inputs critical for animal development and physiology. Impairment of cilium structure or function leads to a spectrum of diseases called ciliopathies.

Key Concepts

  • The centrosome typically contains a centriole pair, the mother and its daughter, and the pericentriolar material (PCM).
  • Centrioles have a ninefold radial symmetry and are required for organising a functional centrosome.
  • The PCM is a large multi‐protein complex that regulates microtubule (MT) assembly at centrosomes in dividing and nondividing cells.
  • Centrioles duplicate only once each cell cycle, and the protein kinase PLK4 is a key early regulator of centriole duplication and biogenesis.
  • The cartwheel at the proximal end of the centriole is assembled early in centriole biogenesis, and its ninefold symmetry is determined by the intrinsic properties of the key structural protein Sas‐6.
  • The centrosome is involved in the asymmetric division of stem cells.
  • In nondividing cells, the basal body, a modified mother centriole, serves as a platform for organising the MT‐based axoneme, forming a primary or motile cilium.
  • Most vertebrate cells contain a primary cilium that is critical for signalling pathways including Hedgehog (Hh) signalling and left–right asymmetry designation during development.
  • Centrosomal and ciliary dysfunctions have been linked to two types of diseases: microcephaly/primordial dwarfisms, and ciliopathies, respectively.

Keywords: centriole; centrosome; pericentriolar material; basal body; cilium; cell cycle; microtubules; ciliopathies; microcephaly; MCPH

Figure 1. Structural elements of the centrosome. In an interphase (early G1) somatic cell, the typical animal centrosome contains a pair of centrioles, a mother and a daughter, each composed of nine triplet microtubules (MTs) that make ninefold symmetric cylinder structure. Distal and subdistal appendages decorate only the mother centriole. Linker fibres provide cohesion between the centriole pair. The pericentriolar material (PCM), where MT nucleation occurs, is organised into toroid layers and radial struts that surround the mother centriole. Shown here is one model of interphase PCM deduced from superresolution microscopy. Sometime during G1, the daughter centriole also gains PCM (not shown). Reproduced with permission from Jodi Slade © Florida State University College of Medicine.
Figure 2. Signalling function of the cilium and its ultrastructure. (a) Example signalling pathway to cytoplasmic and nuclear targets in the primary cilium. In Hedgehog (Hh) signal transduction, for example, transcription factors translocate from the cilium into the nucleus and activate target genes following activation of the pathway. (b) Structure of the cilium. From its distal end, the basal body (a mature mother centriole) templates the MT‐based axoneme. The axoneme in primary cilia generally contains no central MT pairs (9 + 0), compared to that in motile cilia (9 + 2). Cross‐sections of the cilium structure at different apical–basal positions are depicted in the boxes. Pericentriolar material (PCM) is illustrated without the detail shown in Figure. Acting as a ‘gate’, the transition zone, with its characteristic Y‐linkers and ciliary necklace, regulates trafficking of molecules between the cilium and the cytoplasm. Distal appendages on the basal body are modified and become the transition fibres at the transition zone during ciliogenesis. intraflagellar transport (IFT) complexes traffic building blocks to facilitate axoneme assembly and maintenance. Different motor proteins carrying IFT complexes (white) and cargo proteins (orange and cyan) ‘walk’ up (kinesin motor‐red) or down (dynein motor‐blue) the axoneme in anterograde or retrograde transport, respectively. Reproduced with permission from Jodi Slade © Florida State University College of Medicine.
Figure 3. The centrosome cycle. (a) Overview of the centrosome events that occur during the cell cycle. Interphase PCM around mother centrioles is excluded from the image for simplicity. (b) Detailed steps of centriole duplication and the key proteins involved. In late G1 phase, initiation of the procentriole occurs at the side of the mother centriole by PLK4 and Cep152. In early S phase, Sas‐6, Cep135, CPAP (Sas‐4) and STIL promote assembly of the cartwheel at the initiation site. In late S/early G2 phase, triplet MTs assemble and elongate around the cartwheel. Cep120/CPAP complex and CP110 regulate centriole length. Reproduced with permission from Jodi Slade © Florida State University College of Medicine. (c) Sas‐6 serves as the backbone structure for cartwheel assembly. Protein structure of Sas‐6 homodimer that assembles into a rod through coiled‐coil interactions (far left image; box in middle left image). The amino‐terminal head domains of Sas‐6 homodimers join to form the inner ring of the cartwheel hub, with nine rods (cartwheel spokes) radiating outward (middle left image). This structure serves as a scaffold for localisation of additional proteins to form the cartwheel (middle and far right images). Reproduced from Hirono, 2014 © M. Hirono. (d) Regulation of biogenesis ensures only one centriole duplication per cell cycle. PLK4 overexpression causes centriole amplification, where multiple daughter centrioles (centrin‐centriole marker) grow from each mother centriole as seen in this microscopic image. Inset shows centrin signals at two mother centrioles, each surrounded by six centrin‐labelled daughters. Scale bar is 10 µm. Image was reproduced and modified from (Franck et al., 2011) © PLoS One and used under CC BY 4.0.
Figure 4. Mutations in genes that encode the key proteins involved in centriole biogenesis and PCM assembly cause inherited developmental disorders. (a) During brain development, neural progenitors divide asymmetrically. Image on the left shows a larval brain neuroblast undergoing asymmetric division. Miranda (red) is involved in asymmetric division by anchoring neuronal cell fate determinants to the basal side of the cell. The PCM (white) is larger on the opposite (apical) side. Centrosome amplification may lead to abnormal cell division. The pair of images on the right are examples of normal (left) and multipolar (right) spindle formation in spermatocytes undergoing meiosis. Images courtesy of Yiming Zheng and Ling‐Rong Kao. (b) Mutations in centrosome genes lead to reduced growth in the brain and/or body, as seen in primary microcephaly or primordial dwarfisms. Top images show magnetic resonance imaging (MRI) skull scans from a normal individual and one from a microcephalic individual due to mutation in ASPM, an MCPH gene (Table). As a result of reduced brain size, a sloping forehead occurs with microcephaly. In addition to smaller brain size, primordial dwarfism also causes reduced overall stature. MRI image was reproduced from (Unknown, 2004) and used under CC BY 2.5. Other illustration by Jodi Slade.
Figure 5. Ciliary dysfunctions lead to ciliopathies. (a) Mutations in ciliary and basal body proteins may cause defects in cilium structure, assembly and/or function, thereby impairing critical processes such as intercellular signalling. Collectively, the spectrum of syndromes with a basis in cilium impairment are called ciliopathies. (b) Common phenotypes shared among ciliopathies. Associated with mutations in ciliary genes, polycystic kidney disease results in the growth of multiple cysts in the kidney and ultimately kidney failure. Polydactyly is a developmental condition with extra fingers and/or toes and has been associated with the disruption in Hh signalling. is the result of randomised left–right asymmetry designation during development, in which positioning of internal organs is reversed. Retinal degeneration caused by defects in specialised cilia in the eye leads to progressive loss of vision. One common type of degeneration is retinitis pigmentosa, where affected individuals lose area of vision from outside‐in (tunnel vision). Additional common phenotypes that are not represented are obesity, skeletal defects, hepatobiliary disease, neural tube developmental defects and cognitive defects. One or more of these cilium‐based phenotypes will occur, depending on the type and severity of the ciliopathy. Reproduced with permission from Jodi Slade © Florida State University College of Medicine.
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Further Reading

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Buchwalter, Rebecca A, Chen, Jieyan V, Zheng, Yiming, and Megraw, Timothy L(Feb 2016) Centrosome in Cell Division, Development and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020872]