Small organelle, big responsibility: the role of centrosomes in development and disease

Abstract

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

Quantitative analysis of human centrosome architecture by targeted proteomics and fluorescence imaging

“…In addition to their role in nucleating centrosome assembly, fully mature centrioles also function as basal bodies for the formation of cilia and flagella (Ishikawa & Marshall, 2011; Bornens, 2012). Numerical and structural aberrations in centrioles and centrosomes have been implicated in human disease, including cancer, microcephaly, dwarfism, and ciliopathies (Nigg & Raff, 2009; Zyss & Gergely, 2009; Bettencourt‐Dias et al , 2011; Ishikawa & Marshall, 2011; Chavali et al , 2014; Jana et al , 2014; Gonczy, 2015). …”

The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis

“…In proliferating cells, centrioles duplicate exactly once per cell cycle through the formation of one new centriole close to the proximal end of each pre-existing centriole (Azimzadeh and Bornens, 2007;Firat-Karalar and Stearns, 2014;Nigg and Stearns, 2011). Proper control of centriole biogenesis is crucial for embryogenesis, tissue homeostasis and genome stability (Bettencourt-Dias et al, 2011;Godinho and Pellman, 2014;Chavali et al, 2014;Nigg et al, 2014). Dysfunction of the centriole-ciliary apparatus and/or centrosomes is implicated in the etiology of ciliopathies, brain diseases, dwarfism and cancer (Bettencourt-Dias et al, 2011;Godinho and Pellman, 2014;Hildebrandt et al, 2011;Nigg and Raff, 2009;Thornton and Woods, 2009).…”

Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

“…In support of this possibility, neurogenic cells with impaired regulation of centriole duplication are predisposed to mitotic delay or chromosomal aneuploidy leading to a microcephaly and/or retinal phenotype in the patient. 12 Indeed, a mouse model of centrosome amplification manifests microcephaly. 13 PLK4 has a kinase domain at its amino terminal and three PB domains mediating centriole localization and homodimerization at its carboxyl terminal.…”