Ataxin-2 binding protein 1 is a context-specific positive regulator of Notch signaling during neurogenesis in<i>Drosophila melanogaster</i>

Shukla, Jay Prakash; Deshpande, Girish; Shashidhara, L.S.

doi:10.1242/dev.140657

Cited by 12 publications

(25 citation statements)

References 67 publications

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“…ppk23 is a modifier of flies' ability to track odors during free flight, but not a modifier of odorless flight [140]. Our results support a role for ppk23 in modifying flight, along with all but eight (Or46a, Ten-a), and transcription factors (A2bp1/ Rbfox1, CG42741, twi) [141,142], several of which had significant epistatic interactions of their own. Of these, CG10936 is proposed to be involved in sensory perception [142], but has limited annotations otherwise.…”

Section: Important Implications For Acid Sensing Ion Channels In Fligsupporting

confidence: 51%

Natural variation in the regulation of neurodevelopmental genes modifies flight performance inDrosophila

Spierer

Mossman

Smith

et al. 2020

Preprint

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The winged insects of the order Diptera are colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, like dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of variation for flight performance. Accordingly, we sought to uncover the genetic modifiers of flight using a measure of flies’ reaction and response to an abrupt drop in a vertical flight column. We conducted an association study using 197 of the Drosophila Genetic Reference Panel (DGRP) lines, and identified a combination of additive and marginal variants, epistatic interactions, whole genes, and enrichment across interaction networks. We functionally validated 13 of these candidate genes’ (Adgf-A/Adgf-A2/CG32181, bru1, CadN, CG11073, CG15236, CG9766, CREG, Dscam4, form3, fry, Lasp/CG9692, Pde6, Snoo) contribution to flight, two of which (fry and Snoo) also validate a whole gene analysis we introduce for the DGRP: PEGASUS_flies. Overall, our results suggest modifiers of muscle and wing morphology, and peripheral and central nervous system assembly and function are all important for flight performance. Additionally, we identified ppk23, an Acid Sensing Ion Channel (ASIC) homolog, as an important hub for epistatic interactions. These results represent a snapshot of the genetic modifiers affecting drop-response flight performance in Drosophila, with implications for other insects. It also draws connections between genetic modifiers of performance and BMP signaling and ASICs as targets for treating neurodegeneration and neurodysfunction.Author summaryInsect flight is a widely recognizable phenotype of winged insects, hence the name: flies. While fruit flies, or Drosophila melanogaster, are a genetically tractable model, flight performance is a highly integrative phenotype, making it challenging to comprehensively identify the genetic modifiers that contribute to its genetic architecture. Accordingly, we screened 197 Drosophila Genetic Reference Panel lines for their ability to react and respond to an abrupt drop. Using several computational tools, we successfully identified several additive, marginal, and epistatic variants, as well as whole genes and altered sub-networks of gene-gene and protein-protein interaction networks, demonstrating the benefits of using multiple methodologies to elucidate the genetic architecture of complex traits more generally. Many of these significant genes and variants mapped to regions of the genome that affect development of sensory and motor neurons, wing and muscle development, and regulation of transcription factors. We also introduce PEGASUS_flies, a Drosophila-adapted version of the PEGASUS platform first used in human studies, to infer gene-level significance of association based on the distribution of individual variant P-values. Our results contribute to the debate over the relative importance of individual, additive factors and epistatic, or higher order, interactions, in the mapping of genotype to phenotype.

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Section: Important Implications For Acid Sensing Ion Channels In Fligsupporting

confidence: 51%

Natural variation in the regulation of neurodevelopmental genes modifies flight performance inDrosophila

Spierer

Mossman

Smith

et al. 2020

Preprint

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“…Rbfox1 binding to introns causes context-dependent exon retention or skipping, depending on if it binds upstream or downstream of an alternative exon (Fukumura et al, 2007;Nakahata and Kawamoto, 2005), while 3'-UTR binding is reported to modulate mRNA stability (Carreira-Rosario et al, 2016). Rbfox1 may additionally influence transcription networks by binding transcriptional regulators (Shukla et al, 2017;Usha and Shashidhara, 2010;Wei et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Rbfox1 is required for myofibril development and maintaining fiber-type specific isoform expression inDrosophilamuscles

Nikonova

Kamble

Mukherjee

et al. 2021

Preprint

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Protein isoform transitions confer distinct properties on muscle fibers and are regulated predominantly by differential transcription and alternative splicing. RNA-binding Fox protein 1 (Rbfox1) can affect both transcript levels and splicing, and is known to control skeletal muscle function. However, the detailed mechanisms by which Rbfox1 contributes to normal muscle development and physiology remain obscure. In this study, we report that Rbfox1 contributes to the generation of adult muscle diversity in Drosophila. Rbfox1 is differentially expressed in tubular and fibrillar muscle fiber types. RNAi knockdown of Rbfox1 leads to a loss of flight, climbing and jumping ability, as well as eclosion defects. Myofibers in knockdown muscle are frequently torn, and sarcomeres are hypercontracted. These defects arise from mis-regulation of fiber-type specific gene and splice isoform expression, notably loss of an IFM-specific isoform of Troponin-I that is critical for regulating myosin activity. We find that Rbfox1 influences mRNA transcript levels through 1) direct binding of 3'-UTRs of target transcripts as well as 2) through regulation of myogenic transcription factors, including Mef2, Exd and Salm. Moreover, Rbfox1 modulates splice isoform expression through 1) direct regulation of target splice events in structural genes and 2) regulation of the CELF-family RNA-binding protein Bruno1. Our data indicate that cross-regulatory interactions observed between FOX and CELF family RNA-binding proteins in vertebrates are conserved between their counterparts, Rbfox1 and Bruno1 in flies. Rbfox1 thus affects muscle development by regulation of both fiber-type specific gene and gene isoform expression dynamics of identity genes and structural proteins.

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“…Moreover, Septin 7 was identified as a novel ERK3-interacting protein by using a Ras recruitment system, and evidence showed that Sept7, ERK3 and MK5 exist in the same complex and, together with Kal7, are of physiological relevance in neuronal plasticity by regulating dendritic spine formation (63). Furthermore, Ataxin-2 was described as a positive regulator of Notch signaling (64), which may maintain NF-κB activity by direct interaction with p50/c-Rel in the nucleus (65). Thus, we can conclude that there is an indirect association with the current and previous results due to the overlapping functions and interactions of multiple proteins involved in the NF-κB and MAPK signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of the effect of the polyphenol pentagalloyl glucose on proteins involved in neurodegenerative diseases in activated BV‑2 microglial cells

2019

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Neuroinflammation and microglial activation are two important hallmarks of neurodegenerative diseases. Continuous microglial activation may cause the release of several cytotoxic molecules, including many cytokines that are involved in the inflammatory process. Therefore, attenuating inflammation caused by activated microglia may be an approach for the therapeutic management of neurodegenerative diseases. In addition, many studies have reported that polyphenol pentagalloyl glucose (1,2,3,4,6-penta-O-galloyl-β-D-glucose; PGG) is a molecule with potent anti-inflammatory effects, such as inhibiting the release of proinflammatory cytokines. Our previous studies revealed that PGG attenuated the expression of two inflammatory cytokines (murine monocyte chemoattractant protein-5 and pro-metalloproteinase-9) in lipopolysaccharide/interferon γ-activated BV-٢ microglial cells. Additionally, PGG modulated the NF-κB and MAPK signaling pathways by altering genes and proteins, which may affect the MAPK cascade and NF-κB activation. The aim of the present study was to investigate the ability of PGG to modulate the expression of proteins released in activated BV-2 microglial cells, which may be involved in the pathological process of inflammation and neurodegeneration. Proteomic analysis of activated BV-2 cells identified 17 proteins whose expression levels were significantly downregulated by PGG, including septin-7, ataxin-2, and adenylosuccinate synthetase isozyme 2 (ADSS). These proteins were previously described as being highly expressed in neurodegenerative diseases and/or involved in the signaling pathways associated with the formation and growth of neuronal connections and the control of Alzheimer's disease pathogenesis. The inhibitory effect of PGG on ataxin-2, septin-7 and ADSS was further confirmed at the protein and transcriptional levels. Therefore, the obtained results suggest that PGG, with its potent inhibitory effects on ataxin-2, septin-7 and ADSS, may have potential use in the therapeutic management of neurodegenerative diseases.

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Ataxin-2 binding protein 1 is a context-specific positive regulator of Notch signaling during neurogenesis inDrosophila melanogaster

Cited by 12 publications

References 67 publications

Natural variation in the regulation of neurodevelopmental genes modifies flight performance inDrosophila

Natural variation in the regulation of neurodevelopmental genes modifies flight performance inDrosophila

Rbfox1 is required for myofibril development and maintaining fiber-type specific isoform expression inDrosophilamuscles

Proteomic analysis of the effect of the polyphenol pentagalloyl glucose on proteins involved in neurodegenerative diseases in activated BV‑2 microglial cells

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