The ciliopathy-associated proteins Cep290 and BBS4 localize to cytoplasmic particles called centriolar satellites, yet the significance of this association is unknown. A new component of satellites, Cep72, is identified. Its role in the regulation of Cep290 and BBS4 is described, as are developmental defects resulting from loss of satellites in zebrafish.
Autosomal recessive primary microcephaly (MCPH) is a congenital disorder characterized by significantly reduced brain size and mental retardation. Nine genes are currently known to be associated with the condition, all of which encode centrosomal or spindle pole proteins. MCPH is associated with a reduction in proliferation of neural progenitors during fetal development. The cellular mechanisms underlying the proliferation defect, however, are not fully understood. The zebrafish retinal neuroepithelium provides an ideal system to investigate this question. Mutant or morpholino-mediated knockdown of three known MCPH genes (stil, aspm and wdr62) and a fourth centrosomal gene, odf2, which is linked to several MCPH proteins, results in a marked reduction in head and eye size. Imaging studies reveal a dramatic rise in the fraction of proliferating cells in mitosis in all cases, and time-lapse microscopy points to a failure of progression through prometaphase. There was also increased apoptosis in all the MCPH models but this appears to be secondary to the mitotic defect as we frequently saw mitotically arrested cells disappear, and knocking down p53 apoptosis did not rescue the mitotic phenotype, either in whole retinas or clones.
Protein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.
The centrosome and cilium are organelles with important roles in microtubule organisation, cell division, cell signalling, embryogenesis and tissue homeostasis. The two organelles are mutually exclusive. The centriole/basal body is found at the core of the centrosome (centriole) or at the base of the cilium (basal body) and to change which organelle is present in a cell requires modification to the centriole/basal body both in terms of composition and sub-cellular localisation. While many protein components required for centrosome and cilium biogenesis have been described, there are far fewer known inhibitors of ciliogenesis. Here, we show that a protein called BCAP and labelled in the sequence databases as ODF2-like (ODF2L) is a ciliation inhibitor. We show that it is a centriolar satellite protein. Furthermore, our data suggest that BCAP exists as two isoforms with subtly different roles in inhibition of ciliogenesis. Both are required to prevent ciliogenesis and one additionally controls cilium length after ciliogenesis has completed.
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