Deterministic Splicing of is Regulated by Muscleblind

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2019 Feb 13

PMID 30746474

Citations 7

Authors

Joshua Shing Shun Li

S Sean Millard

Affiliations

Soon will be listed here.

Abstract

Alternative splicing increases the proteome diversity crucial for establishing the complex circuitry between trillions of neurons. To provide individual cells with different repertoires of protein isoforms, however, this process must be regulated. Previously, we found that the mutually exclusive alternative splicing of produces two isoforms (A and B) with unique binding properties. This splicing event is cell type specific, and the transmembrane proteins that it generates are crucial for the development of axons, dendrites, and synapses. Here, we show that Muscleblind (Mbl) controls alternative splicing. Mbl represses isoform A and promotes the selection of isoform B. mutants exhibit phenotypes also observed in flies engineered to express a single isoform. Consistent with this, expression is cell type specific and correlates with the splicing of isoform B. Our study demonstrates how the regulated expression of a splicing factor is sufficient to provide neurons with unique protein isoforms crucial for development.

Citing Articles

The Role of Genetic Variation in Shaping Phenotypic Responses to Diet in Aging .

Bak N, Mackay T, Morgante F, Nielsen K, Nielsen J, Kristensen T bioRxiv. 2025; .

PMID: 39868103 PMC: 11761520. DOI: 10.1101/2025.01.09.632132.

A nociceptor-specific RNAi screen in larvae identifies RNA-binding proteins that regulate thermal nociception.

Dyson A, Gajjar G, Hoffman K, Lewis D, Palega S, Rangel Silva E PeerJ. 2025; 13:e18857.

PMID: 39866556 PMC: 11759608. DOI: 10.7717/peerj.18857.

MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans.

Lee H, Lim H, He H, Lau C, Zheng C PLoS Genet. 2024; 20(10):e1011276.

PMID: 39423233 PMC: 11524483. DOI: 10.1371/journal.pgen.1011276.

larval motor patterning relies on regulated alternative splicing of .

Odierna G, Kerwin S, Shin G, Millard S Front Mol Neurosci. 2024; 17:1415207.

PMID: 39092203 PMC: 11292952. DOI: 10.3389/fnmol.2024.1415207.

Identifying new players in structural synaptic plasticity through interrogation.

Xiao C, MAngale P, Wang S, Lemieux A, Thomson T iScience. 2023; 26(11):108048.

PMID: 37876812 PMC: 10590816. DOI: 10.1016/j.isci.2023.108048.

References

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

Irion U . Drosophila muscleblind codes for proteins with one and two tandem zinc finger motifs. PLoS One. 2012; 7(3):e34248. PMC: 3315501. DOI: 10.1371/journal.pone.0034248. View

Ule J, Jensen K, Ruggiu M, Mele A, Ule A, Darnell R . CLIP identifies Nova-regulated RNA networks in the brain. Science. 2003; 302(5648):1212-5. DOI: 10.1126/science.1090095. View

McMahon A, Rahman R, Jin H, Shen J, Fieldsend A, Luo W . TRIBE: Hijacking an RNA-Editing Enzyme to Identify Cell-Specific Targets of RNA-Binding Proteins. Cell. 2016; 165(3):742-53. PMC: 5027142. DOI: 10.1016/j.cell.2016.03.007. View

Li L, Yu Z, Teng X, Bonini N . RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature. 2008; 453(7198):1107-11. PMC: 2574630. DOI: 10.1038/nature06909. View

Nern A, Pfeiffer B, Rubin G . Optimized tools for multicolor stochastic labeling reveal diverse stereotyped cell arrangements in the fly visual system. Proc Natl Acad Sci U S A. 2015; 112(22):E2967-76. PMC: 4460454. DOI: 10.1073/pnas.1506763112. View

Millard S, Flanagan J, Pappu K, Wu W, Zipursky S . Dscam2 mediates axonal tiling in the Drosophila visual system. Nature. 2007; 447(7145):720-4. PMC: 2691714. DOI: 10.1038/nature05855. View

Cerro-Herreros E, Fernandez-Costa J, Sabater-Arcis M, Llamusi B, Artero R . Derepressing muscleblind expression by miRNA sponges ameliorates myotonic dystrophy-like phenotypes in Drosophila. Sci Rep. 2016; 6:36230. PMC: 5090246. DOI: 10.1038/srep36230. View

Houseley J, Garcia-Casado Z, Pascual M, Paricio N, ODell K, Monckton D . Noncanonical RNAs from transcripts of the Drosophila muscleblind gene. J Hered. 2006; 97(3):253-60. DOI: 10.1093/jhered/esj037. View

10.

McKee A, Minet E, Stern C, Riahi S, Stiles C, Silver P . A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain. BMC Dev Biol. 2005; 5:14. PMC: 1199591. DOI: 10.1186/1471-213X-5-14. View

11.

Lah G, Shun Li J, Millard S . Cell-specific alternative splicing of Drosophila Dscam2 is crucial for proper neuronal wiring. Neuron. 2014; 83(6):1376-88. DOI: 10.1016/j.neuron.2014.08.002. View

12.

Iijima T, Iijima Y, Witte H, Scheiffele P . Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1. J Cell Biol. 2014; 204(3):331-42. PMC: 3912522. DOI: 10.1083/jcb.201310136. View

13.

Lee T, Luo L . Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron. 1999; 22(3):451-61. DOI: 10.1016/s0896-6273(00)80701-1. View

14.

Ashwal-Fluss R, Meyer M, Pamudurti N, Ivanov A, Bartok O, Hanan M . circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014; 56(1):55-66. DOI: 10.1016/j.molcel.2014.08.019. View

15.

Artero R, Prokop A, Paricio N, Begemann G, Pueyo I, Mlodzik M . The muscleblind gene participates in the organization of Z-bands and epidermal attachments of Drosophila muscles and is regulated by Dmef2. Dev Biol. 1998; 195(2):131-43. DOI: 10.1006/dbio.1997.8833. View

16.

Machuca-Tzili L, Buxton S, Thorpe A, Timson C, Wigmore P, Luther P . Zebrafish deficient for Muscleblind-like 2 exhibit features of myotonic dystrophy. Dis Model Mech. 2011; 4(3):381-92. PMC: 3097459. DOI: 10.1242/dmm.004150. View

17.

Funada M, Hara H, Sasagawa H, Kitagawa Y, Kadowaki T . A honey bee Dscam family member, AbsCAM, is a brain-specific cell adhesion molecule with the neurite outgrowth activity which influences neuronal wiring during development. Eur J Neurosci. 2007; 25(1):168-80. DOI: 10.1111/j.1460-9568.2006.05270.x. View

18.

Tomioka M, Naito Y, Kuroyanagi H, Iino Y . Splicing factors control C. elegans behavioural learning in a single neuron by producing DAF-2c receptor. Nat Commun. 2016; 7:11645. PMC: 4876481. DOI: 10.1038/ncomms11645. View

19.

Bargiela A, Llamusi B, Cerro-Herreros E, Artero R . Two enhancers control transcription of Drosophila muscleblind in the embryonic somatic musculature and in the central nervous system. PLoS One. 2014; 9(3):e93125. PMC: 3965525. DOI: 10.1371/journal.pone.0093125. View

20.

Underwood J, Boutz P, Dougherty J, Stoilov P, Black D . Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals. Mol Cell Biol. 2005; 25(22):10005-16. PMC: 1280273. DOI: 10.1128/MCB.25.22.10005-10016.2005. View