Genetic strategies to tackle neurological diseases in fruit flies

Şentürk, Mümine; Bellen, Hugo J.

doi:10.1016/j.conb.2017.10.017

Cited by 66 publications

(49 citation statements)

References 71 publications

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“…45,46 Later, the D. melanogaster model was used to expand this theory to include that lifespan is both heritable and plastic. 4 Normal aging has also been studied at the genome-wide level. 13,[51][52][53][54] Despite the lack of a closed circulatory system, even tissues such as heart muscle change with age in a similar manner as human cardiac aging.…”

Section: Drosophila Melanogaster In Aging Studiesmentioning

confidence: 99%

“…These D. melanogaster models of neurodegenerative disease have assisted our understanding of neurodegenerative pathology, and also facilitate high-throughput screening for disease modifiers that can be translated into better therapeutics. 4 Normal aging has also been studied at the genome-wide level. The study of the transcriptome of 14 different Drosophila species with varied life-span suggested additive small effects of many genes, instead of strong effect of a few.…”

Section: Drosophila Melanogaster In Aging Studiesmentioning

confidence: 99%

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Social behavior and aging: A fly model

Brenman-Suttner

Yost

Frame

et al. 2019

Genes Brain and Behavior

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The field of behavioral genetics has recently begun to explore the effect of age on social behaviors. Such studies are particularly important, as certain neuropsychiatric disorders with abnormal social interactions, like autism and schizophrenia, have been linked to older parents. Appropriate social interaction can also have a positive impact on longevity, and is associated with successful aging in humans. Currently, there are few genetic models for understanding the effect of aging on social behavior and its potential transgenerational inheritance. The fly is emerging as a powerful model for identifying the basic molecular mechanisms underlying neurological and neuropsychiatric disorders. In this review, we discuss these recent advancements, with a focus on how studies in Drosophila melanogaster have provided insight into the effect of aging on aspects of social behavior, including across generations.

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Section: Drosophila Melanogaster In Aging Studiesmentioning

confidence: 99%

Section: Drosophila Melanogaster In Aging Studiesmentioning

confidence: 99%

Social behavior and aging: A fly model

Brenman-Suttner

Yost

Frame

et al. 2019

Genes Brain and Behavior

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“…However, none of these variants have been modeled in vivo in part, due to a gap in our understanding of the function of TAFs during brain development. By demonstrating that TAFs are required for NSC cell cycle progression, NSC cell polarity, and act to prevent premature differentiation while not affecting survival, our work provides a foundation for future studies aimed at uncovering the causative variants in these disorders (55).…”

Section: Cells (Escs) As Inducible Depletion Of Taf8 Resulted In Escmentioning

confidence: 86%

Distinct gene-selective roles for a network of core promoter factors inDrosophilaneural stem cell identity

Neves

Eisenman

2018

Preprint

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Running title: Role of core promoter factors in Drosophila neural stem cell identity. AbstractThe transcriptional mechanisms that allow neural stem cells (NSC) to balance selfrenewal with differentiation are not well understood. Employing an in vivo RNAi screen we identify here NSC-TAFs, a subset of nine TATA-binding protein associated factors (TAFs), as NSC identity genes in Drosophila. We found that depletion of NSC-TAFs results in decreased NSC clone size, reduced proliferation, defective cell polarity and increased hypersensitivity to cell cycle perturbation, without affecting NSC survival.Integrated gene expression and genomic binding analyses revealed that NSC-TAFs function with both TBP and TRF2, and that NSC-TAF-TBP and NSC-TAF-TRF2 shared target genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identity in vivo by promoting cell cycle progression and NSC cell polarity as well as by restraining premature differentiation. Because pathogenic variants in a subset of TAFs have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders. Author summaryThe brains of many animal species are built with brain stem cells. Having too many brain stem cells can lead to brain tumors whereas too few can lead to birth defects such as microcephaly. A number of next generation sequencing studies have implicated proteins referred to as TATA-box-binding protein associated factors (TAFs) in human neurological disorders including microcephaly, but prior to this study, their function in brain development was unknown. Here we use brain stem cells, known as neural stem cells (NSCs), from the fruit fly Drosophila melanogaster as a model system to decipher how TAFs control brain stem cell identity. By combining genetics and low-input genomics, we show that TAFs directly control NSC cell division and cell polarity but do not appear to be required for NSC survival. We further show that TAFs accomplish these functions by associating either with their canonical partner TBP (TATA-binding protein) or the related protein TRF2. In summary, our study reveals unexpected and gene-selective functions of a unique subset of TAFs and their binding partners, which could inform future studies that seek to model human neurological disorders associated with TAFs. 0

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“…This provides a means for rigorous quality assessment of the genetic reagent and, when combined with mutant and/or truncated forms of the UAS-GOI cDNA, facilitates structure-function analysis. In addition, a UAS-human-homologue cDNA of the GOI permits humanization of the flies and assessment of human variants (Bellen and Yamamoto, 2015;Kanca et al, 2017;Şentürk and Bellen, 2018;Chao et al, 2017;Yoon et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

An efficient CRISPR-based strategy to insert small and large fragments of DNA using short homology arms

Kanca

Zirin

García-Marqués

et al. 2019

Preprint

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We previously reported a CRISPR-mediated knock-in strategy into introns of Drosophila genes, generating an attP-FRT-SA-T2A-GAL4-polyA-3XP3-EGFP-FRT-attP transgenic library for multiple uses (Lee et al., 2018b). The method relied on double stranded DNA (dsDNA) homology donors with ~1 kb homology arms. Here, we describe three new simpler ways to edit genes in flies. We create single stranded DNA (ssDNA) donors using PCR and add 100 nt of homology on each side of an integration cassette, followed by enzymatic removal of one strand. Using this method, we generated GFP-tagged proteins that mark organelles in S2 cells. We then describe two dsDNA methods using cheap synthesized donors flanked by 100 nt homology arms and gRNA target sites cloned into a plasmid. Upon injection, donor DNA (1 to 5 kb) is released from the plasmid by Cas9. The cassette integrates efficiently and precisely in vivo. The approach is fast, cheap, and scalable.

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Genetic strategies to tackle neurological diseases in fruit flies

Cited by 66 publications

References 71 publications

Social behavior and aging: A fly model

Social behavior and aging: A fly model

Distinct gene-selective roles for a network of core promoter factors inDrosophilaneural stem cell identity

An efficient CRISPR-based strategy to insert small and large fragments of DNA using short homology arms

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