The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Liu, Min; Li, Yajuan; Liu, Aiguo; Li, Ruifeng; Su, Ying; Du, Juan; Li, Cheng; Zhu, Alan Jian

doi:10.7554/elife.17200

Cited by 12 publications

(11 citation statements)

References 88 publications

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“…In this regard, it is notable that levels of the Vang family member Vangl2 are elevated in the hippocampal proteome of Zc3h14 knockout mice ( Rha et al 2017 ), and that depletion of ZC3H14 from cultured N2A cells leads to intron retention in the PSD95 mRNA ( Morris and Corbett 2018 ), which encodes a postsynaptic guanylate kinase required for activity-dependent synaptic plasticity (reviewed in Xu 2011 ). Intriguingly, the fly PSD95 homolog Discs Large-1 (Dlg1) controls canonical Wg signaling in wing tissue by stabilizing Dsh protein ( Liu et al 2016 ). In light of these observations in mammalian systems, the corresponding Drosophila mRNAs vang and dlg1 represent candidate Nab2 targets that may contribute to Nab2-PCP genetic interactions documented in this study.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

Lee

Corgiat

Rounds

et al. 2020

G3 Genes|Genomes|Genetics

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Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability in humans. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental mechanisms that underlie defective axonogenesis in Nab2 mutants remain undefined. Nab2 null phenotypes in the brain mushroom bodies (MBs) resemble defects caused by alleles that disrupt the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells via a non-canonical arm of the Wnt/Wg pathway. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP mutant alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR>Nab2) and, subsequently, for modification of a viability defect among Nab2 nulls. Multiple PCP alleles dominantly modify GMR>Nab2 eye roughening and a subset rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Collectively, these genetic interactions identify the PCP pathway as a potential target of the Nab2 RNA-binding protein in developing eye and wing tissues and suggest that PCP signaling could contribute to neurological defects that result from loss of Drosophila Nab2 or its vertebrate ortholog ZC3H14.

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Section: Discussionmentioning

confidence: 99%

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

Lee

Corgiat

Rounds

et al. 2020

G3 Genes|Genomes|Genetics

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“…The proteins of the core EJC and RNPS1 positively regulate the splicing of cell polarity determinant Dlg1 transcript, thus controlling Wnt signalling. In connection with this, knockdown of the core EJC or RNPS1, reduced the expression of Dlg1 and Dsh, resulting in reduced Wnt signalling 55 .…”

Section: Roles Of the Asap Components In Mrna Metabolismmentioning

confidence: 95%

“…Specifically, many functional roles of RNPS1 with EJC have been demonstrated. For example, it was recently shown that the core EJC (eIF4A3; Mago, homolog of human MAGOH; Y14) and RNPS1 are crucial for Wingless (Wg)/Wnt signalling by regulating the splicing of gene discs large 1 ( dlg1 ) 55 . Wnt signalling is essential for cell proliferation, cell migration, cell polarity, pattern formation, stem cell maintenance and adult tissue homeostasis.…”

Section: Roles Of the Asap Components In Mrna Metabolismmentioning

confidence: 99%

Multifaceted Regulation of Gene Expression by the Apoptosis- and Splicing-Associated Protein Complex and Its Components

Deka

Singh

2017

Int. J. Biol. Sci.

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The differential deposition of RNA-binding proteins (RBPs) on pre-mRNA mediates the processes of gene expression. One of the complexes containing RBPs that play a crucial part in RNA metabolism is the apoptosis-and splicing-associated protein (ASAP) complex. In this review, we present a summary of the structure of ASAP complex and its localization. Also, we discuss the findings by different groups on various functions of the subunits of the ASAP complex in RNA metabolism. The subunits of the ASAP complex are RNPS1, Acinus and SAP18. Originally, the ASAP complex was thought to link RNA processing with apoptosis. Further studies have shown the role of these components in RNA metabolism of cells, including transcription, splicing, translation and nonsense-mediated mRNA decay (NMD). In transcription, RNPS1 is involved in preventing the formation of R-loop, while Acinus and SAP18 suppress transcription with the help of histone deacetylase. On the one hand, individual components of the ASAP complex, namely RNPS1 and Acinus act as splicing activators, whereas on the other hand, in-vitro assay shows that the ASAP complex behaves as splicing repressor. In addition, the individual members of the ASAP complex associates with the exon junction complex (EJC) to play roles in splicing and translation. RNPS1 increases the translation efficiency by participating in the 3'end processing and polysome association of mRNAs. Similarly, during NMD RNPS1 aids in the recruitment of decay factors by interacting with EJC.

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“…Nab2 may modify PCP-regulated developmental processes indirectly through post- (LIU et al 2016). In light of these observations, the corresponding fly vang and dlg1 mRNAs are candidate Nab2 targets that may contribute to Nab2-PCP genetic interactions documented in this study.…”

Section: Discussionmentioning

confidence: 60%

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

Moberg

Lee

Corbett

et al. 2019

Preprint

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Running title: Nab2 interacts with planar cell polarity factors in Drosophila 34 35 ABSTRACT 46 Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a 47 non-syndromic form of autosomal recessive intellectual disability. Studies in Drosophila have defined 48 roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory 49 due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and 50 coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental 51 pathways regulated by Nab2 remain poorly defined. Structural defects in Nab2 null brains resemble 52 defects observed upon disruption of the planar cell polarity (PCP) pathway, which regulates planar 53 orientation of static and motile cells. A kinked bristle phenotype in surviving Nab2 mutant adults 54 additionally suggests a defect in F-actin polymerization and bundling, which is also a PCP-regulated 55 processes. To test for Nab2-PCP genetic interactions, a collection of PCP loss-of-function alleles was 56 screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye 57 (GMR-Nab2) and subsequently for modification of Nab2 null phenotypes. Multiple PCP alleles 58 dominantly modify GMR-Nab2 eye roughening and a subset of these alleles also rescue low survival 59 and thoracic bristle kinking in Nab2 zygotic nulls. Moreover, alleles of two X-linked PCP factors, 60 dishevelled (dsh) and β amyloid protein precursor-like (Appl), rescue GMR-Nab2 eye roughening in 61 male progeny derived from hemizygous dsh or Appl mutant fathers, suggesting an additional effect 62 inherited through the male germline. These findings demonstrate a consistent pattern of Nab2-PCP 63 genetic interactions that suggest molecular links between Nab2 and the PCP pathway in the developing 64 eye, wing and germline. 65 66 67 68 3 69 70 Mutations in genes that encode RNA-binding proteins often lead to tissue-specific disease pathology, 71 particularly within the brain and nervous system (reviewed in CASTELLO et al. 2013). Inactivating 72 mutations in the human ZC3H14 gene, which encodes a ubiquitously expressed zinc-finger, poly(A) 73 RNA-binding protein, are linked to a monogenic form of non-syndromic autosomal recessive 74 intellectual disability (reviewed in FASKEN et al. 2019). The ZC3H14 protein and its homologs in the 75 budding yeast S. cerevisiae and fruit fly Drosophila melanogaster (Nab2 in both species) interact with 76 A-rich motifs in RNAs and restrict the length of mRNA polyadenosine (poly(A)) tails. Phenotypes 77 associated with loss of Nab2/ZC3H14 are thus predicted to arise due to defects in post-transcriptional 78 control mechanisms that involve poly(A)-dependent mRNA processing and nuclear export, stability, 79 localization, and/or translation.80Studies in Drosophila indicate that Nab2/ZC3H14 share a conserved and necessary function in 81 brain neurons (PAK et al. 2011; KELLY et al. 2014). Neuron-specific Na...

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The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Cited by 12 publications

References 88 publications

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

Multifaceted Regulation of Gene Expression by the Apoptosis- and Splicing-Associated Protein Complex and Its Components

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway inDrosophila melanogaster

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