Hidden RNA pairings counteract the “first-come, first-served” splicing principle to drive stochastic choice in
            <i>Dscam1</i>
            splice variants

Dong, Haiyang; Xu, Bingbing; Guo, Pengjuan; Zhang, Jian; Yang, Xi; Li, Lei; Fu, Ying; Shi, Jilong; Zhang, Shixin; Zhu, Yanda; Shi, Yang; Zhou, Feng; Bian, Lina; You, Wendong; Shi, Feng; Yang, Xiaofeng; Huang, Jianhua; He, Haihuai; Jin, Yongfeng

doi:10.1126/sciadv.abm1763

Cited by 7 publications

(5 citation statements)

References 60 publications

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“…These data indicate that these differences at same position persist in the same mutants and in different genetic backgrounds (Figure 7D; Figure S6A). Because similar branching defects have been observed in mutants with the deletion of docking site of exon 6 cluster where Ig3 variant composition was altered,(Dong et al, 2022) we conclude that the defects seen in Dscam1 Δ9uD mutants derives solely from the altered composition of Dscam1 Ig 7 variants.…”

Section: Resultssupporting

confidence: 72%

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

Zhang

Yang

Dong

et al. 2022

Preprint

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Drosophila Dscam1 encodes ten thousand of cell recognition molecules via alternative splicing, which is required for nervous function. However, the underlying mechanism has not fully understood. Here we revealed extensive noncanonical functions of Dscam1 isoform diversity in neuronal wiring. We generated a series of allelic cis mutations in Dscam1, encoding normal number of isoforms albeit with altered isoform composition. Despite normal dendritic self-avoidance and self/non-self discrimination in da neurons, which is consistent with canonical self-avoidance model, these mutants exhibited strikingly distinct spectra of phenotypic defects in three classes of neurons: up to ~60% defects in mushroom bodies, a significantly increased branching and growth in da neurons, and mild axonal branching defects in mechanosensory neurons. These data suggest that proper Dscam1 isoform composition is required for axon and dendrite growth in diverse neurons. This unprecedented splicing-tuned regulation unlocks new insights into the molecular mechanisms that Dscam1 isoform diversity is engaged in.

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Section: Resultssupporting

confidence: 72%

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

Zhang

Yang

Dong

et al. 2022

Preprint

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“…6 D and S6 ). Since identical branching defects were observed in mutants with deletion of docking sites in the exon 6 cluster with altered composition of the Ig3 variant ( 33 ), we conclude that the branching defects seen in Dscam1 Δ9uD mutants mainly originate from the altered composition of the Dscam1 Ig7 variants.…”

Section: Resultsmentioning

confidence: 51%

“…Slit binding and subsequent increased Dscam1 dephosphorylation by RPTP69D modulated Dscam1 signaling to locally control axon branch growth in circuit formation ( 40 ). This variable domain specificity is also supported by evidence that a cluster-specific deletion of the docking site in the exon 4 cluster results in only a subtle MB defect (<4%) ( 27 ), whereas a deletion of the docking site in the exon 6 cluster results in ∼5% MB defect ( 33 ). In contrast, our present study shows that altered composition of Ig7 variants causes as high as 60% of MB defects.…”

Section: Discussionmentioning

confidence: 73%

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

et al. 2023

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Drosophila Dscam1 encodes tens of thousands of cell recognition molecules via alternative splicing, which are required for neural function. A canonical self-avoidance model seems to provide a central mechanistic basis for Dscam1 functions in neuronal wiring. Here, we reveal extensive noncanonical functions of Dscam1 isoforms in neuronal wiring. We generated a series of allelic cis mutations in Dscam1, encoding a normal number of isoforms, but with an altered isoform composition. Despite normal dendritic self-avoidance and self/non-self discrimination in dendritic arborization (da) neurons, which is consistent with the canonical self-avoidance model, these mutants exhibited strikingly distinct spectra of phenotypic defects in the three types of neurons: up to ∼60% defects in mushroom bodies, a significant increase in branching and growth in da neurons, and mild axonal branching defects in mechanosensory neurons. Remarkably, the altered isoform composition resulted in increased dendrite growth yet inhibited axon growth. Moreover, reducing Dscam1 dosage exacerbated axonal defects in mushroom bodies and mechanosensory neurons, but reverted dendritic branching and growth defects in da neurons. This splicing-tuned regulation strategy suggests that axon and dendrite growth in diverse neurons cell-autonomously require Dscam1 isoform composition. These findings provide important insights into the functions of Dscam1 isoforms in neuronal wiring.

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“…For example, since exon cluster 9 has the largest spectra of variation among different variants, we infer that exon 9 isoforms have the highest specificity. This idea is supported by genetic evidence that altering the variant composition by deleting docking sites in exon 4 or 6 clusters leads to <5% subtle to mild MB defects [ 27 , 36 ]. However, deleting upstream docking sites in the exon 9 cluster causes up to 60% of MB defects [ 28 ].…”

Section: Discussionmentioning

confidence: 98%

A systematic CRISPR screen reveals redundant and specific roles for Dscam1 isoform diversity in neuronal wiring

Dong,

Yang,

et al. 2023

PLoS Biol

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Drosophila melanogaster Down syndrome cell adhesion molecule 1 (Dscam1) encodes 19,008 diverse ectodomain isoforms via the alternative splicing of exon 4, 6, and 9 clusters. However, whether individual isoforms or exon clusters have specific significance is unclear. Here, using phenotype–diversity correlation analysis, we reveal the redundant and specific roles of Dscam1 diversity in neuronal wiring. A series of deletion mutations were performed from the endogenous locus harboring exon 4, 6, or 9 clusters, reducing to 396 to 18,612 potential ectodomain isoforms. Of the 3 types of neurons assessed, dendrite self/non-self discrimination required a minimum number of isoforms (approximately 2,000), independent of exon clusters or isoforms. In contrast, normal axon patterning in the mushroom body and mechanosensory neurons requires many more isoforms that tend to associate with specific exon clusters or isoforms. We conclude that the role of the Dscam1 diversity in dendrite self/non-self discrimination is nonspecifically mediated by its isoform diversity. In contrast, a separate role requires variable domain- or isoform-related functions and is essential for other neurodevelopmental contexts, such as axonal growth and branching. Our findings shed new light on a general principle for the role of Dscam1 diversity in neuronal wiring.

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Hidden RNA pairings counteract the “first-come, first-served” splicing principle to drive stochastic choice in Dscam1 splice variants

Cited by 7 publications

References 60 publications

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

A systematic CRISPR screen reveals redundant and specific roles for Dscam1 isoform diversity in neuronal wiring

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