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1.
Dis Model Mech ; 17(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38214058

RESUMO

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. Although adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of disease caused by this virus, which includes microcephaly. In this study, we generated a toolkit to ectopically express ZIKV proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We used this toolkit to identify phenotypes and potential host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins caused scorable phenotypes, such as overall lethality, gross morphological defects, reduced brain size and neuronal function defects. We further used this system to identify strain-dependent phenotypes that may have contributed to the increased pathogenesis associated with the outbreak of ZIKV in the Americas in 2015. Our work demonstrates the use of Drosophila as an efficient in vivo model to rapidly decipher how pathogens cause disease and lays the groundwork for further molecular study of ZIKV pathogenesis in flies.


Assuntos
Microcefalia , Infecção por Zika virus , Zika virus , Animais , Zika virus/metabolismo , Drosophila , Drosophila melanogaster , Microcefalia/epidemiologia , Microcefalia/etiologia
2.
bioRxiv ; 2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37163061

RESUMO

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. While adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of symptoms caused by this virus including microcephaly. In this study, we generated a toolkit to ectopically express Zika viral proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We use this toolkit to identify phenotypes and host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins cause scorable phenotypes, such as overall lethality, gross morphological defects, reduced brain size, and neuronal function defects. We further use this system to identify strain-dependent phenotypes that may contribute to the increased pathogenesis associated with the more recent outbreak of ZIKV in the Americas. Our work demonstrates Drosophila's use as an efficient in vivo model to rapidly decipher how pathogens cause disease and lays the groundwork for further molecular study of ZIKV pathogenesis in flies.

3.
Cell Rep ; 38(11): 110517, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35294868

RESUMO

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Drosophila , Transtornos do Neurodesenvolvimento , Receptores de Glicina , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Transtorno Autístico/genética , Drosophila/genética , Predisposição Genética para Doença , Humanos , Transtornos do Neurodesenvolvimento/genética , Receptores de Glicina/genética
4.
Elife ; 92020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909715

RESUMO

Partitioning of mRNAs into ribonucleoprotein (RNP) granules supports diverse regulatory programs within the crowded cytoplasm. At least two types of RNP granules populate the germ plasm, a cytoplasmic domain at the posterior of the Drosophila oocyte and embryo. Germ granules deliver mRNAs required for germline development to pole cells, the germ cell progenitors. A second type of RNP granule, here named founder granules, contains oskar mRNA, which encodes the germ plasm organizer. Whereas oskar mRNA is essential for germ plasm assembly during oogenesis, we show that it is toxic to pole cells. Founder granules mediate compartmentalized degradation of oskar during embryogenesis to minimize its inheritance by pole cells. Degradation of oskar in founder granules is temporally and mechanistically distinct from degradation of oskar and other mRNAs during the maternal-to-zygotic transition. Our results show how compartmentalization in RNP granules differentially controls fates of mRNAs localized within the same cytoplasmic domain.


Assuntos
Compartimento Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Células Germinativas/citologia , Células Germinativas/metabolismo , Proteólise , Animais , Movimento Celular , Grânulos Citoplasmáticos/metabolismo , Drosophila melanogaster/metabolismo , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Feminino , Fatores de Iniciação de Peptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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