Abstract
Microtubules that assemble the mitotic spindle are generated by centrosomal nucleation, chromatin-mediated nucleation, and nucleation from the surface of other microtubules mediated by the augmin complex. Impairment of centrosomal nucleation in apical progenitors of the developing mouse brain induces p53-dependent apoptosis and causes non-lethal microcephaly. Whether disruption of non-centrosomal nucleation has similar effects is unclear. Here, we show, using mouse embryos, that conditional knockout of the augmin subunit Haus6 in apical progenitors led to spindle defects and mitotic delay. This triggered massive apoptosis and abortion of brain development. Co-deletion of Trp53 rescued cell death, but surviving progenitors failed to organize a pseudostratified epithelium, and brain development still failed. This could be explained by exacerbated mitotic errors and resulting chromosomal defects including increased DNA damage. Thus, in contrast to centrosomes, augmin is crucial for apical progenitor mitosis, and, even in the absence of p53, for progression of brain development.
Highlights
In contrast to the centrosomal nucleation pathway, augmin is crucial for apical progenitor mitosis, and, even in the absence of p53, for progression of brain development. 41 Introduction Spindle assembly crucially depends on microtubule nucleation by the J-tubulin ring complex (JTuRC)
Our results show that contrary to centrosomal microtubule nucleation, the augmin-dependent pathway is essential for apical progenitor mitotic progression and survival, and for brain development
Previous work has shown that the augmin complex is composed of eight subunits and that depletion of any subunit interferes with augmin assembly and function
Summary
Spindle assembly crucially depends on microtubule nucleation by the J-tubulin ring complex (JTuRC). During mitosis JTuRC generates microtubules through three different pathways: centrosomal nucleation, chromatin-mediated nucleation, and nucleation from the surface of other microtubules [1,2,3]. The latter mechanism is mediated by the augmin complex and has been referred to as a microtubule amplification mechanism [4,5,6,7]. Augmin binds to the lattice of microtubules generated by the centrosome- and chromatin-dependent pathways and, through recruitment of JTuRC, promotes nucleation of additional microtubules that grow as branches from these sites [8,9,10,11]. While functional studies in Xenopus egg extract and cultured cell models have generated a wealth of information regarding the types of spindle defects that occur when specific nucleation pathways are compromised, how these defects impinge on cell fate and development remains poorly defined
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