SAM68 Regulates Neuronal Activity-dependent Alternative Splicing of Neurexin-1

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Dec 27

PMID 22196734

Citations 168

Authors

Takatoshi Iijima

Karen Wu

Harald Witte

Yoko Hanno-Iijima

Timo Glatter

Stephane Richard

Peter Scheiffele

Affiliations

Soon will be listed here.

Abstract

The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.

Citing Articles

RBM4-mediated intron excision of Hsf1 induces BDNF for cerebellar foliation.

Shen C, Tsai Y, Chou S, Chang Y, Tarn W Commun Biol. 2024; 7(1):1712.

PMID: 39738787 PMC: 11685446. DOI: 10.1038/s42003-024-07328-6.

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.

A comparison of basal and activity-dependent exon splicing in cortical-patterned neurons of human and mouse origin.

Dando O, McQueen J, Burr K, Kind P, Chandran S, Hardingham G Front Mol Neurosci. 2024; 17:1392408.

PMID: 39268251 PMC: 11390650. DOI: 10.3389/fnmol.2024.1392408.

Reverse engineering neuron type-specific and type-orthogonal splicing-regulatory networks using single-cell transcriptomes.

Moakley D, Campbell M, Anglada-Girotto M, Feng H, Califano A, Au E bioRxiv. 2024; .

PMID: 38915499 PMC: 11195221. DOI: 10.1101/2024.06.13.597128.

Epigenetic control of adaptive or homeostatic splicing during interval-training activities.

Liu L, Nguyen H, Das U, Ogunsola S, Yu J, Lei L Nucleic Acids Res. 2024; 52(12):7211-7224.

PMID: 38661216 PMC: 11229381. DOI: 10.1093/nar/gkae311.

References

Rozic-Kotliroff G, Zisapel N . Ca2+ -dependent splicing of neurexin IIalpha. Biochem Biophys Res Commun. 2006; 352(1):226-30. DOI: 10.1016/j.bbrc.2006.11.008. View

Matter N, Herrlich P, Konig H . Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature. 2002; 420(6916):691-5. DOI: 10.1038/nature01153. View

Rossi P, De Filippi G, Armano S, Taglietti V, DAngelo E . The weaver mutation causes a loss of inward rectifier current regulation in premigratory granule cells of the mouse cerebellum. J Neurosci. 1998; 18(10):3537-47. PMC: 6793145. View

Valacca C, Bonomi S, Buratti E, Pedrotti S, Baralle F, Sette C . Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J Cell Biol. 2010; 191(1):87-99. PMC: 2953442. DOI: 10.1083/jcb.201001073. View

Batsche E, Yaniv M, Muchardt C . The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol. 2005; 13(1):22-9. DOI: 10.1038/nsmb1030. View

Henao-Mejia J, Liu Y, Park I, Zhang J, Sanford J, He J . Suppression of HIV-1 Nef translation by Sam68 mutant-induced stress granules and nef mRNA sequestration. Mol Cell. 2009; 33(1):87-96. PMC: 2644331. DOI: 10.1016/j.molcel.2008.11.024. View

Baudouin S, Scheiffele P . SnapShot: Neuroligin-neurexin complexes. Cell. 2010; 141(5):908, 908.e1. DOI: 10.1016/j.cell.2010.05.024. View

Rozic G, Lupowitz Z, Piontkewitz Y, Zisapel N . Dynamic changes in neurexins' alternative splicing: role of Rho-associated protein kinases and relevance to memory formation. PLoS One. 2011; 6(4):e18579. PMC: 3075264. DOI: 10.1371/journal.pone.0018579. View

Songyang Z, Lu K, Kwon Y, Tsai L, Filhol O, Cochet C . A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol. 1996; 16(11):6486-93. PMC: 231650. DOI: 10.1128/MCB.16.11.6486. View

10.

Li J, Ashley J, Budnik V, Bhat M . Crucial role of Drosophila neurexin in proper active zone apposition to postsynaptic densities, synaptic growth, and synaptic transmission. Neuron. 2007; 55(5):741-55. PMC: 2039911. DOI: 10.1016/j.neuron.2007.08.002. View

11.

Mellor J, Merlo D, Jones A, Wisden W, Randall A . Mouse cerebellar granule cell differentiation: electrical activity regulates the GABAA receptor alpha 6 subunit gene. J Neurosci. 1998; 18(8):2822-33. PMC: 6792580. View

12.

Lin Q, Taylor S, Shalloway D . Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains. J Biol Chem. 1997; 272(43):27274-80. DOI: 10.1074/jbc.272.43.27274. View

13.

Zhang C, Zhang Z, Castle J, Sun S, Johnson J, Krainer A . Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev. 2008; 22(18):2550-63. PMC: 2546699. DOI: 10.1101/gad.1703108. View

14.

Li Q, Lee J, Black D . Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci. 2007; 8(11):819-31. DOI: 10.1038/nrn2237. View

15.

Stoss O, Novoyatleva T, Gencheva M, Olbrich M, Benderska N, Stamm S . p59(fyn)-mediated phosphorylation regulates the activity of the tissue-specific splicing factor rSLM-1. Mol Cell Neurosci. 2004; 27(1):8-21. DOI: 10.1016/j.mcn.2004.04.011. View

16.

Cohen S, Greenberg M . Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu Rev Cell Dev Biol. 2008; 24:183-209. PMC: 2709812. DOI: 10.1146/annurev.cellbio.24.110707.175235. View

17.

Di Fruscio M, Chen T, Richard S . Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc Natl Acad Sci U S A. 1999; 96(6):2710-5. PMC: 15834. DOI: 10.1073/pnas.96.6.2710. View

18.

Siddiqui T, Pancaroglu R, Kang Y, Rooyakkers A, Craig A . LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci. 2010; 30(22):7495-506. PMC: 2896269. DOI: 10.1523/JNEUROSCI.0470-10.2010. View

19.

de Wit J, Sylwestrak E, OSullivan M, Otto S, Tiglio K, Savas J . LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron. 2010; 64(6):799-806. PMC: 2829666. DOI: 10.1016/j.neuron.2009.12.019. View

20.

Galarneau A, Richard S . The STAR RNA binding proteins GLD-1, QKI, SAM68 and SLM-2 bind bipartite RNA motifs. BMC Mol Biol. 2009; 10:47. PMC: 2697983. DOI: 10.1186/1471-2199-10-47. View