RESUMO
In metazoans, organisms arising from a fertilized egg, the embryo will develop through multiple series of cell divisions, both symmetric and asymmetric, leading to differentiation. Aurora A is a serine threonine kinase highly involved in such divisions. While intensively studied at the cell biology level, its function in the development of a whole organism has been neglected. Here we investigated the pleiotropic effect of Aurora A loss-of-function in Drosophila larval early development. We report that Aurora A is required for proper larval development timing control through direct and indirect means. In larval tissues, Aurora A is required for proper symmetric division rate and eventually development speed as we observed in central brain, wing disc and ring gland. Moreover, Aurora A inactivation induces a reduction of ecdysteroids levels and a pupariation delay as an indirect consequence of ring gland development deceleration. Finally, although central brain development is initially restricted, we confirmed that brain lobe size eventually increases due to additive phenotypes: delayed pupariation and over-proliferation of cells with an intermediate cell-identity between neuroblast and ganglion mother cell resulting from defective asymmetric neuroblast cell division.
Assuntos
Aurora Quinase A/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila/embriologia , Larva/metabolismo , Animais , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Encéfalo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Divisão Celular/fisiologia , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Pleiotropia Genética/genética , Larva/fisiologia , Mutação com Perda de Função/genética , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Fuso Acromático/metabolismoRESUMO
Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials. The varying efficiencies and particularities of these drugs raise several questions that are explored in this review: is Aurora A even a good target? What biomarkers can we use to measure its activity in vivo? How can we improve the Aurora A-inhibiting drugs?
