Plk4 and Aurora A cooperate in the initiation of acentriolar spindle assembly in mammalian oocytes.

Leah Bury,Patrick A Eyers,Magdalena Zernicka-Goetz,Paula A Coelho,David M Glover,Claire E Eyers,Angela Simeone,Samantha Ferries

doi:10.1083/jcb.201606077

Abstract

Establishing the bipolar spindle in mammalian oocytes after their prolonged arrest is crucial for meiotic fidelity and subsequent development. In contrast to somatic cells, the first meiotic spindle assembles in the absence of centriole-containing centrosomes. Ran-GTP can promote microtubule nucleation near chromatin, but additional unidentified factors are postulated for the activity of multiple acentriolar microtubule organizing centers in the oocyte. We now demonstrate that partially overlapping, nonredundant functions of Aurora A and Plk4 kinases contribute to initiate acentriolar meiosis I spindle formation. Loss of microtubule nucleation after simultaneous chemical inhibition of both kinases can be significantly rescued by drug-resistant Aurora A alone. Drug-resistant Plk4 can enhance Aurora A-mediated rescue, and, accordingly, Plk4 can phosphorylate and potentiate the activity of Aurora A in vitro. Both kinases function distinctly from Ran, which amplifies microtubule growth. We conclude that Aurora A and Plk4 are rate-limiting factors contributing to microtubule growth as the acentriolar oocyte resumes meiosis.

Highlights

Proper spindle assembly is critical for chromosome alignment and segregation during meiotic and mitotic cell divisions
In considering which factors might promote microtubule nucleation in the oocyte upon resumption of meiosis, we first asked whether they might be similar to those required for spindle formation from acentriolar microtubule organizing centers (MTOCs) in the early mouse embryo (Coelho et al, 2013)
The gradient of Ran-GTP around chromatin is critical to promote spindle formation in the absence of centrosomes in many systems (O’Connell and Khodjakov, 2007), it is not essential for formation of the first bipolar meiotic spindle upon meiotic resumption in the acentriolar mouse oocyte, even though it does contribute to the increase in density of microtubules after nuclear envelope breakdown (NEBD) (Dumont et al, 2007; Schuh and Ellenberg, 2007)

Summary

Introduction

Proper spindle assembly is critical for chromosome alignment and segregation during meiotic and mitotic cell divisions. Defects in spindle formation during this division correlate with chromosome segregation errors and are a leading cause of infertility and embryonic aneuploidy (Hassold and Hunt, 2001). Centrosomes do, enhance mitotic fidelity (Delattre and Gönczy, 2004; Zamora and Marshall, 2005; McCoy et al, 2015). In most metazoans, centrioles are naturally eliminated during oogenesis before female meiosis (Delattre and Gönczy, 2004) high fidelity of chromosome transmission during meiosis I in the oocyte, essential to correctly establish the generation, relies on acentrosomal spindle assembly (Heald et al, 1996)

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