RESUMEN
Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP's activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades Musculares/genética , Proteínas Serina-Treonina Quinasas/genética , Proteína que Contiene Valosina/genética , Adenosina Trifosfatasas/genética , Animales , Autofagia/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/patología , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Ratones , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Fosforilación/genética , Estrés Fisiológico/genética , Ubiquitina/genéticaRESUMEN
BACKGROUND: The oosome is the germline determinant in the wasp Nasonia vitripennis and is homologous to the polar granules of Drosophila. Despite a common evolutionary origin and developmental role, the oosome is morphologically quite distinct from polar granules. It is a solid sphere that migrates within the cytoplasm before budding out and forming pole cells. RESULTS: To gain an understanding of both the molecular basis of oosome development and the conserved essential features of germ plasm, we quantified and compared transcript levels between embryo fragments that contained the oosome and those that did not. The identity of the differentially localized transcripts indicated that Nasonia uses a distinct set of molecules to carry out conserved germ plasm functions. In addition, functional testing of a sample of localized transcripts revealed potentially novel mechanisms of ribonucleoprotein assembly and pole cell cellularization in the wasp. CONCLUSIONS: Our results demonstrate that the composition of germ plasm varies significantly within Holometabola, as very few mRNAs share localization to the oosome and polar granules. Some of this variability appears to be related to the unique properties of the oosome relative to the polar granules in Drosophila, and some may be related to differences in pole formation between species. This work will serve as the basis for further investigation into the patterns of germline determinant evolution among insects, the molecular basis of the unique properties of the oosome, and the incorporation of novel components into developmental networks.
Asunto(s)
Embrión no Mamífero/metabolismo , Células Germinativas/metabolismo , Avispas/embriología , Avispas/genética , Animales , ARN Mensajero/metabolismo , TranscriptomaRESUMEN
The establishment of the germline is essential for sexually reproducing organisms. In animals, there are two major strategies to specify the germline: maternal provision and zygotic induction. The molecular basis of the maternal provision mode has been well characterized in several model organisms (fly, frog, fish, and nematode), while that of the zygotic induction mode has mainly been studied in mammalian models such as the mouse. Shifts in germline determination modes occur unexpectedly frequently and many such shifts have occurred several times among insects. Given their general tractability and rapidly increasing genomic and genetic tools applicable to many species, the insects present a uniquely powerful model system for understanding major transitions in reproductive strategies, and developmental processes in general.