Centrosome maturation - in tune with the cell cycle.

Centrosomes are the main microtubule-organizing centres, playing essential roles in the organization of the cytoskeleton during interphase, and in the mitotic spindle, which controls chromosome segregation, during cell division. Centrosomes also act as the basal body of cilia, regulating cilium length and affecting extracellular signal reception as well as the integration of intracellular signalling pathways. Centrosomes are self-replicative and duplicate once every cell cycle to generate two centrosomes. The core support structure of the centrosome consists of two molecularly distinct centrioles. The mother (mature) centriole exhibits accessory appendages and is surrounded by both pericentriolar material and centriolar satellites, structures that the daughter (immature) centriole lacks. In this Review, we discuss what is currently known about centrosome duplication, its dialogue with the cell cycle and the sequential acquisition of specific components during centriole maturation. We also describe our current understanding of the mature centriolar structures that are required to build a cilium. Altogether, the built-in centrosome asymmetries that stem from the two centrosomes inheriting molecularly different centrioles sets the foundation for cell division being an intrinsically asymmetric process.

A centrosomal view of CNS growth.

Embryonic development of the central nervous system (CNS) requires the proliferation of neural progenitor cells to be tightly regulated, allowing the formation of an organ with the right size and shape. This includes regulation of both the spatial distribution of mitosis and the mode of cell division. The centrosome, which is the main microtubule-organizing centre of animal cells, contributes to both of these processes. Here, we discuss the impact that centrosome-mediated control of cell division has on the shape of the overall growing CNS. We also review the intrinsic properties of the centrosome, both in terms of its molecular composition and its signalling capabilities, and discuss the fascinating notion that intrinsic centrosomal asymmetries in dividing neural progenitor cells are instructive for neurogenesis. Finally, we discuss the genetic links between centrosome dysfunction during development and the aetiology of microcephaly.

Cell intercalation driven by SMAD3 underlies secondary neural tube formation.

Body axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodeling of the tail bud. Although it is clear how neuromesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead to de novo lumen formation and that culminate in the formation of a 3-dimensional, neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-ß/SMAD3 signaling is required for secondary neural tube formation. Our analysis describes the events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. We show that the resolution of a single, centrally positioned lumen, which occurs through the intercalation of central cells, requires SMAD3/Yes-associated protein (YAP) activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, among the most frequent birth defects detected in humans.

Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis.

Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. Although the enzymatic activity of ZikV-NS5 appears to be dispensable, the amino acids Y25, K28, and K29 that are involved in NS5 oligomerization are essential for localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation for therapies that target ZikV-NS5 multimerization and prevent the developmental malformations associated with congenital Zika syndrome.