Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice

Xiaoming Wang1, Qiong Xu1, Alexandra L. Bey2, Yoonji Lee1, Yong‐Hui Jiang1
1Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, 27710, Durham, NC, USA
2Department of Neurobiology, Duke University School of Medicine, 27710, Durham, NC, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Sheng M, Kim E: The Shank family of scaffold proteins. J Cell Sci. 2000, 113 (Pt 11): 1851-1856.

Ehlers MD: Synapse structure: glutamate receptors connected by the shanks. Curr Biol. 1999, 9: R848-R850. 10.1016/S0960-9822(00)80043-3.

Grabrucker AM, Schmeisser MJ, Schoen M, Boeckers TM: Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies. Trends Cell Biol. 2011, 21: 594-603. 10.1016/j.tcb.2011.07.003.

Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF: Coupling of mGluR/homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron. 1999, 23: 583-592. 10.1016/S0896-6273(00)80810-7.

Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, Sheng M: Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron. 1999, 23: 569-582. 10.1016/S0896-6273(00)80809-0.

Uchino S, Wada H, Honda S, Nakamura Y, Ondo Y, Uchiyama T, Tsutsumi M, Suzuki E, Hirasawa T, Kohsaka S: Direct interaction of post-synaptic density-95/Dlg/ZO-1 domain-containing synaptic molecule Shank3 with GluR1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor. J Neurochem. 2006, 97: 1203-1214. 10.1111/j.1471-4159.2006.03831.x.

Verpelli C, Dvoretskova E, Vicidomini C, Rossi F, Chiappalone M, Schoen M, Di Stefano B, Mantegazza R, Broccoli V, Bockers TM, Dityatev A, Sala C: Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. J Biol Chem. 2011, 286: 34839-34850. 10.1074/jbc.M111.258384.

Jiang YH, Ehlers MD: Modeling autism by SHANK gene mutations in mice. Neuron. 2013, 78: 8-27. 10.1016/j.neuron.2013.03.016.

Wilson HL, Wong AC, Shaw SR, Tse WY, Stapleton GA, Phelan MC, Hu S, Marshall J, McDermid HE: Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet. 2003, 40: 575-584. 10.1136/jmg.40.8.575.

Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, S2D Group, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011, 88: 306-316. 10.1016/j.ajhg.2011.02.001.

Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW: Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007, 81: 1289-1297. 10.1086/522590.

Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007, 39: 25-27. 10.1038/ng1933.

Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D, Hawes A, Lewis L, Akbar H, Varghese R, Boerwinkle E, Gibbs RA, Zoghbi HY: Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorder. Hum Mol Genet. 2011, 20 (17): 3366-3375. 10.1093/hmg/ddr243.

Waga C, Okamoto N, Ondo Y, Fukumura-Kato R, Goto Y, Kohsaka S, Uchino S: Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development. Psychiatr Genet. 2011, 21: 208-211. 10.1097/YPG.0b013e328341e069.

Gauthier J, Champagne N, Lafreniere RG, Xiong L, Spiegelman D, Brustein E, Lapointe M, Peng H, Cote M, Noreau A, Hamdan FF, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Joober R, Fathalli F, Mouaffak F, Haghighi AP, Néri C, Dubé MP, Samuels ME, Marineau C, Stone EA, Awadalla P, Barker PA, Carbonetto S, Drapeau P, Rouleau GA, S2D Team: De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A. 2010, 107: 7863-7868. 10.1073/pnas.0906232107.

Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD: Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Molecular Autism. 2010, 1: 15-10.1186/2040-2392-1-15.

Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G: Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011, 472: 437-442. 10.1038/nature09965.

Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH: Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011, 20: 3093-3108. 10.1093/hmg/ddr212.

Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, Janssen AL, Udvardi PT, Shiban E, Spilker C, Balschun D, Skryabin BV, Dieck S, Smalla KH, Montag D, Leblond CS, Faure P, Torquet N, Le Sourd AM, Toro R, Grabrucker AM, Shoichet SA, Schmitz D, Kreutz MR, Bourgeron T, Gundelfinger ED, Boeckers TM: Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature. 2012, 486: 256-260.

Kouser M, Speed HE, Dewey CM, Reimers JM, Widman AJ, Gupta N, Liu S, Jaramillo TC, Bangash M, Xiao B, Worley PF, Powell CM: Loss of predominant shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J Neurosci. 2013, 33: 18448-18468. 10.1523/JNEUROSCI.3017-13.2013.

Lim S, Naisbitt S, Yoon J, Hwang JI, Suh PG, Sheng M, Kim E: Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J Biol Chem. 1999, 274: 29510-29518. 10.1074/jbc.274.41.29510.

Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A: Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet. 2012, 8: e1002521-10.1371/journal.pgen.1002521.

Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF: Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010, 466: 253-257. 10.1038/nature09165.

Waga C, Asano H, Sanagi T, Suzuki E, Nakamura Y, Tsuchiya A, Itoh M, Goto YI, Kohsaka S, Uchino S: Identification of two novel Shank3 transcripts in the developing mouse neocortex. J Neurochem. 2014, 128 (2): 280-293. 10.1111/jnc.12505.

Zhu L, Wang X, Li XL, Towers A, Cao X, Wang P, Bowman R, Yang H, Goldstein J, Li YJ, Jiang YH: Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum Mol Genet. 2014, 23 (6): 1563-1783. 10.1093/hmg/ddt547.

Wang X, Bey AL, Chung L, Krystal AD, Jiang YH: Therapeutic approaches for shankopathies. Dev Neurobiol. 2014, 74: 123-135. 10.1002/dneu.22084.

Kim HJ, Magrane J: Isolation and culture of neurons and astrocytes from the mouse brain cortex. Methods Mol Biol. 2011, 793: 63-75. 10.1007/978-1-61779-328-8_4.

Schneider CA, Rasband WS, Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012, 9: 671-675. 10.1038/nmeth.2089.

Wang XM, Li J, Feng XC, Wang Q, Guan DY, Shen ZH: Involvement of the role of Chk1 in lithium-induced G2/M phase cell cycle arrest in hepatocellular carcinoma cells. J Cell Biochem. 2008, 104: 1181-1191. 10.1002/jcb.21693.

Bockers TM, Mameza MG, Kreutz MR, Bockmann J, Weise C, Buck F, Richter D, Gundelfinger ED, Kreienkamp HJ: Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein alpha-fodrin. J Biol Chem. 2001, 276: 40104-40112. 10.1074/jbc.M102454200.

Ehlers MD: Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci. 2003, 6: 231-242. 10.1038/nn1013.

Flavell SW, Greenberg ME: Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci. 2008, 31: 563-590. 10.1146/annurev.neuro.31.060407.125631.

Fischer A, Sananbenesi F, Mungenast A, Tsai LH: Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci. 2010, 31: 605-617. 10.1016/j.tips.2010.09.003.

Schor IE, Rascovan N, Pelisch F, Allo M, Kornblihtt AR: Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc Natl Acad Sci U S A. 2009, 106: 4325-4330. 10.1073/pnas.0810666106.

Beri S, Tonna N, Menozzi G, Bonaglia MC, Sala C, Giorda R: DNA methylation regulates tissue-specific expression of Shank3. J Neurochem. 2007, 101: 1380-1391. 10.1111/j.1471-4159.2007.04539.x.

Lim S, Sala C, Yoon J, Park S, Kuroda S, Sheng M, Kim E: Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol Cell Neurosci. 2001, 17: 385-397. 10.1006/mcne.2000.0940.

Scott DB, Blanpied TA, Swanson GT, Zhang C, Ehlers MD: An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci. 2001, 21: 3063-3072.

Missler M, Sudhof TC: Neurexins: three genes and 1001 products. Trends Genet. 1998, 14: 20-26. 10.1016/S0168-9525(97)01324-3.

Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T: Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res. 2007, 85: 525-535. 10.1002/jnr.21139.

Lenroot RK, Yeung PK: Heterogeneity within autism spectrum disorders: what have We learned from neuroimaging studies?. Front Hum Neurosci. 2013, 7: 733-

Rice K, Moriuchi JM, Jones W, Klin A: Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children. J Am Acad Child Adolesc Psychiatry. 2012, 51: 238-248. 10.1016/j.jaac.2011.12.017.

Betancur C: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011, 1380: 42-77.

Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008, 9: 341-355. 10.1038/nrg2346.

Szatmari P: Heterogeneity and the genetics of autism. J Psychiatry Neurosci. 1999, 24: 159-165.

Jiang YH, Yuen RK, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, Thiruvahindrapuram B, Thompson A, Uddin M, Walker S, Luo J, Anagnostou E, Zwaigenbaum L, Ring RH: Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet. 2013, 93: 249-263. 10.1016/j.ajhg.2013.06.012.

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW: De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012, 485: 237-241. 10.1038/nature10945.

Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB: De novo gene disruptions in children on the autistic spectrum. Neuron. 2012, 74: 285-299. 10.1016/j.neuron.2012.04.009.

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y: Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012, 485: 242-245. 10.1038/nature11011.