A centrosomal view of CNS growth

Abstract

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.

Lack of adaptation to centriolar defects leads to p53-independent microcephaly in the absence of Cep135

“…Despite the identification of at least 20 MCPH genes causative of primary microcephaly, the cellular basis underlying the neurodevelopmental abnormalities present in patients with most of these specific mutations is still elusive. Interestingly, more than half of MCPH gene products are known to be located at the centrosome or spindle poles, pointing to centrosome dysfunction as one of the main causes of MCPH (Jayaraman, Bae et al, 2018, Saade et al, 2018. The altered mitotic behavior commonly observed in MCPH usually comprises excessive asymmetric cell division of neural progenitors during brain development, impaired neural differentiation or cell death of progenitors, which accounts for a reduced pool of progenitors during development, reduced neuronal output and, as a result, microcephaly (Barbelanne & Tsang, 2014, Jayaraman et al, 2018.…”

“…These changes are not linked with gross anomalies of brain architecture and associate with a primary and selective defect in the production of neurons during development. Several genes mutated in MCPH patients have been identified so far (MCPH1-20), including genes encoding proteins associated with centriole biology or the mitotic spindle such as ASPM (MCPH5) and WDR62 (MCPH2), the two most commonly mutated MCPH genes (Jayaraman, Kodani et al, 2016, Megraw, Sharkey et al, 2011, Saade, Blanco-Ameijeiras et al, 2018, Thornton & Woods, 2009. Centrioles are barrel-shaped, membrane-less organelles which behave as the major microtubule organizing centers (MTOCs) generating key cellular structures such as centrosomes, cilia and flagella.…”

“…These structures recruit several proteins to polymerize a robust pericentriolar matrix (PCM) thereby allowing the generation of a bipolar spindle that ensures the correct segregation of chromosomes to both daughter cells thus avoiding chromosomal instability. Deregulation of centrosome dynamics typically results in variety of cell division defects ultimately affecting neural development (Saade et al, 2018).…”

Evolution of vertebrate spinal cord patterning

“…Furthermore, Shh and Wnt signaling control different stages of the cell cycle through regulation of cyclin D1, E, A, B, with Shh being epistatic to Tcf3/4 (a Wnt‐regulated transcription factor) when regulating cyclin D1 . Cell cycle regulation in neural tube development is more extensively reviewed elsewhere . In addition, another ventral signal, Sema3B, may also regulate progenitor maintenance …”

“…41 Cell cycle regulation in neural tube development is more extensively reviewed elsewhere. 94,95 In addition, another ventral signal, Sema3B, may also regulate progenitor maintenance. 96 While still not fully pieced together, these data suggest regulation of proliferation is complex, involves inputs from both AP and DV signaling pathways, and may vary along both AP and DV axes as well as through developmental time at the same axial location.…”