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Revisiting Dscam diversity: lessons from clustered protocadherins

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Abstract

The complexity of neuronal wiring relies on the extraordinary recognition diversity of cell surface molecules. Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the striking diversity from a complex genomic locus, wherein the former encodes more than 10,000 distinct isoforms via alternative splicing, while the latter employs alternative promoters to attain isoform diversity. These structurally unrelated families show remarkably striking molecular parallels and even similar functions. Recent studies revealed a novel Dscam gene family with tandemly arrayed 5′ cassettes in Chelicerata (e.g., the scorpion Mesobuthus martensii and the tick Ixodes scapularis), similar to vertebrate clustered Pcdhs. Likewise, octopus shows a more remarkable expansion of the Pcdh isoform repertoire than human. These discoveries of Dscam and Pcdh diversification reshape the evolutionary landscape of recognition molecule diversity and provide a greater understanding of convergent molecular strategies for isoform diversity. This article reviews new insights into the evolution, regulatory mechanisms, and functions of Dscam and Pcdh isoform diversity. In particular, the convergence of clustered Dscams and Pcdhs is highlighted.

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References

  1. Sperry RW (1963) Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci USA 50(4):703–710

    Article  CAS  Google Scholar 

  2. Wu Q, Maniatis T (1999) A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97(6):779–790

    Article  CAS  Google Scholar 

  3. Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M, Dixon JE, Zipursky SL (2000) Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101(6):671–684

    Article  CAS  Google Scholar 

  4. Zipursky SL, Sanes JR (2010) Chemoaffinity revisited: dscams, protocadherins, and neural circuit assembly. Cell 143(3):343–353. https://doi.org/10.1016/j.cell.2010.10.009

    Article  CAS  PubMed  Google Scholar 

  5. Tasic B, Nabholz CE, Baldwin KK, Kim Y, Rueckert EH, Ribich SA, Cramer P, Wu Q, Axel R, Maniatis T (2002) Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Mol Cell 10(1):21–33

    Article  CAS  Google Scholar 

  6. Wang X, Su H, Bradley A (2002) Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev 16(15):1890–1905. https://doi.org/10.1101/gad.1004802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen WV, Maniatis T (2013) Clustered protocadherins. Development 140(16):3297–3302. https://doi.org/10.1242/dev.090621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zipursky SL, Grueber WB (2013) The molecular basis of self-avoidance. Annu Rev Neurosci 36:547–568. https://doi.org/10.1146/annurev-neuro-062111-150414

    Article  CAS  PubMed  Google Scholar 

  9. Yue Y, Meng Y, Ma H, Hou S, Cao G, Hong W, Shi Y, Guo P, Liu B, Shi F, Yang Y, Jin Y (2016) A large family of Dscam genes with tandemly arrayed 5′ cassettes in Chelicerata. Nat Commun 7:11252. https://doi.org/10.1038/ncomms11252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cao G, Shi Y, Zhang J, Ma H, Hou S, Dong H, Hong W, Chen S, Li H, Wu Y, Guo P, Shao X, Xu B, Shi F, Meng Y, Jin Y (2018) A chelicerate-specific burst of nonclassical Dscam diversity. BMC Genom 19(1):66. https://doi.org/10.1186/s12864-017-4420-0

    Article  CAS  Google Scholar 

  11. Brites D, Brena C, Ebert D, Du Pasquier L (2013) More than one way to produce protein diversity: duplication and limited alternative splicing of an adhesion molecule gene in basal arthropods. Evolution 67(10):2999–3011. https://doi.org/10.1111/evo.12179

    Article  PubMed  Google Scholar 

  12. Chipman AD, Ferrier DE, Brena C, Qu J, Hughes DS, Schroder R, Torres-Oliva M, Znassi N, Jiang H, Almeida FC, Alonso CR, Apostolou Z, Aqrawi P, Arthur W, Barna JC, Blankenburg KP, Brites D, Capella-Gutierrez S, Coyle M, Dearden PK, Du Pasquier L, Duncan EJ, Ebert D, Eibner C, Erikson G, Evans PD, Extavour CG, Francisco L, Gabaldon T, Gillis WJ, Goodwin-Horn EA, Green JE, Griffiths-Jones S, Grimmelikhuijzen CJ, Gubbala S, Guigo R, Han Y, Hauser F, Havlak P, Hayden L, Helbing S, Holder M, Hui JH, Hunn JP, Hunnekuhl VS, Jackson L, Javaid M, Jhangiani SN, Jiggins FM, Jones TE, Kaiser TS, Kalra D, Kenny NJ, Korchina V, Kovar CL, Kraus FB, Lapraz F, Lee SL, Lv J, Mandapat C, Manning G, Mariotti M, Mata R, Mathew T, Neumann T, Newsham I, Ngo DN, Ninova M, Okwuonu G, Ongeri F, Palmer WJ, Patil S, Patraquim P, Pham C, Pu LL, Putman NH, Rabouille C, Ramos OM, Rhodes AC, Robertson HE, Robertson HM, Ronshaugen M, Rozas J, Saada N, Sanchez-Gracia A, Scherer SE, Schurko AM, Siggens KW, Simmons D, Stief A, Stolle E, Telford MJ, Tessmar-Raible K, Thornton R, van der Zee M, von Haeseler A, Williams JM, Willis JH, Wu Y, Zou X, Lawson D, Muzny DM, Worley KC, Gibbs RA, Akam M, Richards S (2014) The first myriapod genome sequence reveals conservative arthropod gene content and genome organisation in the centipede Strigamia maritima. PLoS Biol 12(11):e1002005. https://doi.org/10.1371/journal.pbio.1002005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Albertin CB, Simakov O, Mitros T, Wang ZY, Pungor JR, Edsinger-Gonzales E, Brenner S, Ragsdale CW, Rokhsar DS (2015) The octopus genome and the evolution of cephalopod neural and morphological novelties. Nature 524(7564):220–224. https://doi.org/10.1038/nature14668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mountoufaris G, Chen WV, Hirabayashi Y, O’Keeffe S, Chevee M, Nwakeze CL, Polleux F, Maniatis T (2017) Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly. Science 356(6336):411–414. https://doi.org/10.1126/science.aai8801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen WV, Nwakeze CL, Denny CA, O’Keeffe S, Rieger MA, Mountoufaris G, Kirner A, Dougherty JD, Hen R, Wu Q, Maniatis T (2017) Pcdhalphac2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science 356(6336):406–411. https://doi.org/10.1126/science.aal3231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yamakawa K, Huot YK, Haendelt MA, Hubert R, Chen XN, Lyons GE, Korenberg JR (1998) DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. Hum Mol Genet 7(2):227–237

    Article  CAS  Google Scholar 

  17. Schmucker D, Chen B (2009) Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes. Genes Dev 23(2):147–156. https://doi.org/10.1101/gad.1752909

    Article  CAS  PubMed  Google Scholar 

  18. Nossa CW, Havlak P, Yue JX, Lv J, Vincent KY, Brockmann HJ, Putnam NH (2014) Joint assembly and genetic mapping of the Atlantic horseshoe crab genome reveals ancient whole genome duplication. Gigascience 3:9. https://doi.org/10.1186/2047-217X-3-9

    Article  PubMed  PubMed Central  Google Scholar 

  19. Armitage SA, Freiburg RY, Kurtz J, Bravo IG (2012) The evolution of Dscam genes across the arthropods. BMC Evol Biol 12:53. https://doi.org/10.1186/1471-2148-12-53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kopelman NM, Lancet D, Yanai I (2005) Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Nat Genet 37(6):588–589. https://doi.org/10.1038/ng1575

    Article  CAS  PubMed  Google Scholar 

  21. Hulpiau P, Van Roy F (2010) New insights into the evolution of metazoan cadherins. Mol Biol Evol 28(1):647–657

    Article  Google Scholar 

  22. Wu Q, Zhang T, Cheng JF, Kim Y, Grimwood J, Schmutz J, Dickson M, Noonan JP, Zhang MQ, Myers RM, Maniatis T (2001) Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res 11(3):389–404. https://doi.org/10.1101/gr.167301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu WP, Yew K, Rajasegaran V, Venkatesh B (2007) Sequencing and comparative analysis of fugu protocadherin clusters reveal diversity of protocadherin genes among teleosts. BMC Evol Biol 7:49. https://doi.org/10.1186/1471-2148-7-49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ravi V, Yu WP, Pillai NE, Lian MM, Tay BH, Tohari S, Brenner S, Venkatesh B (2016) Cyclostomes lack clustered protocadherins. Mol Biol Evol 33(2):311–315. https://doi.org/10.1093/molbev/msv252

    Article  CAS  PubMed  Google Scholar 

  25. Wang ZY, Ragsdale CW (2017) Cadherin genes and evolutionary novelties in the octopus. Semin Cell Dev Biol 69:151–157. https://doi.org/10.1016/j.semcdb.2017.06.007

    Article  CAS  PubMed  Google Scholar 

  26. Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S, Yagi T (2005) Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons. Nat Genet 37(2):171–176. https://doi.org/10.1038/ng1500

    Article  CAS  PubMed  Google Scholar 

  27. Celotto AM, Graveley BR (2001) Alternative splicing of the Drosophila Dscam pre-mRNA is both temporally and spatially regulated. Genetics 159(2):599–608

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Neves G, Zucker J, Daly M, Chess A (2004) Stochastic yet biased expression of multiple Dscam splice variants by individual cells. Nat Genet 36(3):240–246. https://doi.org/10.1038/ng1299

    Article  CAS  PubMed  Google Scholar 

  29. Sun W, You X, Gogol-Doring A, He H, Kise Y, Sohn M, Chen T, Klebes A, Schmucker D, Chen W (2013) Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. EMBO J 32(14):2029–2038. https://doi.org/10.1038/emboj.2013.144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hummel T, Vasconcelos ML, Clemens JC, Fishilevich Y, Vosshall LB, Zipursky SL (2003) Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron 37(2):221–231. https://doi.org/10.1016/S0896-6273(02)01183-2

    Article  CAS  PubMed  Google Scholar 

  31. Zhan XL, Clemens JC, Neves G, Hattori D, Flanagan JJ, Hummel T, Vasconcelos ML, Chess A, Zipursky SL (2004) Analysis of Dscam diversity in regulating axon guidance in Drosophila mushroom bodies. Neuron 43(5):673–686. https://doi.org/10.1016/j.neuron.2004.07.020

    Article  CAS  PubMed  Google Scholar 

  32. He H, Kise Y, Izadifar A, Urwyler O, Ayaz D, Parthasarthy A, Yan B, Erfurth ML, Dascenco D, Schmucker D (2014) Cell-intrinsic requirement of Dscam1 isoform diversity for axon collateral formation. Science 344(6188):1182–1186. https://doi.org/10.1126/science.1251852

    Article  CAS  PubMed  Google Scholar 

  33. Miura SK, Martins A, Zhang KX, Graveley BR, Zipursky SL (2013) Probabilistic splicing of Dscam1 establishes identity at the level of single neurons. Cell 155(5):1166–1177. https://doi.org/10.1016/j.cell.2013.10.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Watson FL, Puttmann-Holgado R, Thomas F, Lamar DL, Hughes M, Kondo M, Rebel VI, Schmucker D (2005) Extensive diversity of Ig-superfamily proteins in the immune system of insects. Science 309(5742):1874–1878. https://doi.org/10.1126/science.1116887

    Article  CAS  PubMed  Google Scholar 

  35. Armitage SAO, Kurtz J, Brites D, Dong Y, Du Pasquier L, Wang HC (2017) Dscam1 in pancrustacean immunity: current status and a look to the future. Front Immunol 8:662. https://doi.org/10.3389/fimmu.2017.00662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hirano K, Kaneko R, Izawa T, Kawaguchi M, Kitsukawa T, Yagi T (2012) Single-neuron diversity generated by Protocadherin-beta cluster in mouse central and peripheral nervous systems. Front Mol Neurosci 5:90. https://doi.org/10.3389/fnmol.2012.00090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaneko R, Kato H, Kawamura Y, Esumi S, Hirayama T, Hirabayashi T, Yagi T (2006) Allelic gene regulation of Pcdh-alpha and Pcdh-gamma clusters involving both monoallelic and biallelic expression in single Purkinje cells. J Biol Chem 281(41):30551–30560. https://doi.org/10.1074/jbc.M605677200

    Article  CAS  PubMed  Google Scholar 

  38. Palmer WJ, Jiggins FM (2015) Comparative genomics reveals the origins and diversity of arthropod immune systems. Mol Biol Evol 32(8):2111–2129. https://doi.org/10.1093/molbev/msv093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Graveley BR (2005) Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123(1):65–73. https://doi.org/10.1016/j.cell.2005.07.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Anastassiou D, Liu H, Varadan V (2006) Variable window binding for mutually exclusive alternative splicing. Genome Biol 7(1):R2. https://doi.org/10.1186/gb-2006-7-1-r2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. May GE, Olson S, McManus CJ, Graveley BR (2011) Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. RNA 17(2):222–229. https://doi.org/10.1261/rna.2521311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yang Y, Zhan L, Zhang W, Sun F, Wang W, Tian N, Bi J, Wang H, Shi D, Jiang Y, Zhang Y, Jin Y (2011) RNA secondary structure in mutually exclusive splicing. Nat Struct Mol Biol 18(2):159–168. https://doi.org/10.1038/nsmb.1959

    Article  CAS  PubMed  Google Scholar 

  43. Yue Y, Yang Y, Dai L, Cao G, Chen R, Hong W, Liu B, Shi Y, Meng Y, Shi F, Xiao M, Jin Y (2016) Long-range RNA pairings contribute to mutually exclusive splicing. RNA 22(1):96–110. https://doi.org/10.1261/rna.053314.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jin Y, Dong H, Shi Y, Bian L (2018) Mutually exclusive alternative splicing of pre-mRNAs. Wiley Interdiscip Rev RNA 9(3):e1468

    Article  Google Scholar 

  45. Olson S, Blanchette M, Park J, Savva Y, Yeo GW, Yeakley JM, Rio DC, Graveley BR (2007) A regulator of Dscam mutually exclusive splicing fidelity. Nat Struct Mol Biol 14(12):1134–1140. https://doi.org/10.1038/nsmb1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang X, Li G, Yang Y, Wang W, Zhang W, Pan H, Zhang P, Yue Y, Lin H, Liu B, Bi J, Shi F, Mao J, Meng Y, Zhan L, Jin Y (2012) An RNA architectural locus control region involved in Dscam mutually exclusive splicing. Nat Commun 3:1255. https://doi.org/10.1038/ncomms2269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463(7280):457–463. https://doi.org/10.1038/nature08909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323

    Article  CAS  Google Scholar 

  49. Yue Y, Li G, Yang Y, Zhang W, Pan H, Chen R, Shi F, Jin Y (2013) Regulation of Dscam exon 17 alternative splicing by steric hindrance in combination with RNA secondary structures. RNA Biol 10(12):1822–1833. https://doi.org/10.4161/rna.27176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith CW, Nadal-Ginard B (1989) Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell 56(5):749–758

    Article  CAS  Google Scholar 

  51. Hirayama T, Yagi T (2017) Regulation of clustered protocadherin genes in individual neurons. Semin Cell Dev Biol 69:122–130. https://doi.org/10.1016/j.semcdb.2017.05.026

    Article  CAS  PubMed  Google Scholar 

  52. Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, Maniatis T (2012) Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-alpha gene expression. Proc Natl Acad Sci USA 109(23):9125–9130. https://doi.org/10.1073/pnas.1205074109

    Article  PubMed  Google Scholar 

  53. Guo Y, Monahan K, Wu H, Gertz J, Varley KE, Li W, Myers RM, Maniatis T, Wu Q (2012) CTCF/cohesin-mediated DNA looping is required for protocadherin alpha promoter choice. Proc Natl Acad Sci USA 109(51):21081–21086. https://doi.org/10.1073/pnas.1219280110

    Article  PubMed  Google Scholar 

  54. Guo Y, Xu Q, Canzio D, Shou J, Li J, Gorkin DU, Jung I, Wu H, Zhai Y, Tang Y, Lu Y, Wu Y, Jia Z, Li W, Zhang MQ, Ren B, Krainer AR, Maniatis T, Wu Q (2015) CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162(4):900–910. https://doi.org/10.1016/j.cell.2015.07.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wojtowicz WM, Flanagan JJ, Millard SS, Zipursky SL, Clemens JC (2004) Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding. Cell 118(5):619–633. https://doi.org/10.1016/j.cell.2004.08.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wojtowicz WM, Wu W, Andre I, Qian B, Baker D, Zipursky SL (2007) A vast repertoire of Dscam binding specificities arises from modular interactions of variable Ig domains. Cell 130(6):1134–1145. https://doi.org/10.1016/j.cell.2007.08.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Meijers R, Puettmann-Holgado R, Skiniotis G, Liu JH, Walz T, Wang JH, Schmucker D (2007) Structural basis of Dscam isoform specificity. Nature 449(7161):487–491. https://doi.org/10.1038/nature06147

    Article  CAS  PubMed  Google Scholar 

  58. Sawaya MR, Wojtowicz WM, Andre I, Qian B, Wu W, Baker D, Eisenberg D, Zipursky SL (2008) A double S shape provides the structural basis for the extraordinary binding specificity of Dscam isoforms. Cell 134(6):1007–1018. https://doi.org/10.1016/j.cell.2008.07.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schreiner D, Weiner JA (2010) Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc Natl Acad Sci USA 107(33):14893–14898. https://doi.org/10.1073/pnas.1004526107

    Article  PubMed  Google Scholar 

  60. Thu CA, Chen WV, Rubinstein R, Chevee M, Wolcott HN, Felsovalyi KO, Tapia JC, Shapiro L, Honig B, Maniatis T (2014) Single-cell identity generated by combinatorial homophilic interactions between alpha, beta, and gamma protocadherins. Cell 158(5):1045–1059. https://doi.org/10.1016/j.cell.2014.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rubinstein R, Thu CA, Goodman KM, Wolcott HN, Bahna F, Mannepalli S, Ahlsen G, Chevee M, Halim A, Clausen H, Maniatis T, Shapiro L, Honig B (2015) Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell 163(3):629–642. https://doi.org/10.1016/j.cell.2015.09.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yagi T (2012) Molecular codes for neuronal individuality and cell assembly in the brain. Front Mol Neurosci 5:45. https://doi.org/10.3389/fnmol.2012.00045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nicoludis JM, Vogt BE, Green AG, Scharfe CP, Marks DS, Gaudet R (2016) Antiparallel protocadherin homodimers use distinct affinity—and specificity-mediating regions in cadherin repeats 1–4. Elife 5:e18449. https://doi.org/10.7554/elife.18449

    Article  PubMed  PubMed Central  Google Scholar 

  64. Goodman KM, Rubinstein R, Thu CA, Bahna F, Mannepalli S, Ahlsen G, Rittenhouse C, Maniatis T, Honig B, Shapiro L (2016) Structural basis of diverse homophilic recognition by clustered alpha- and beta-protocadherins. Neuron 90(4):709–723. https://doi.org/10.1016/j.neuron.2016.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen BE, Kondo M, Garnier A, Watson FL, Puettmann-Holgado R, Lamar DR, Schmucker D (2006) The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila. Cell 125(3):607–620. https://doi.org/10.1016/j.cell.2006.03.034

    Article  CAS  PubMed  Google Scholar 

  66. Hattori D, Demir E, Kim HW, Viragh E, Zipursky SL, Dickson BJ (2007) Dscam diversity is essential for neuronal wiring and self-recognition. Nature 449(7159):223–227. https://doi.org/10.1038/nature06099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hughes ME, Bortnick R, Tsubouchi A, Bäumer P, Kondo M, Uemura T, Schmucker D (2007) Homophilic Dscam interactions control complex dendrite morphogenesis. Neuron 54(3):417–427

    Article  CAS  Google Scholar 

  68. Matthews BJ, Kim ME, Flanagan JJ, Hattori D, Clemens JC, Zipursky SL, Grueber WB (2007) Dendrite self-avoidance is controlled by Dscam. Cell 129(3):593–604. https://doi.org/10.1016/j.cell.2007.04.013

    Article  CAS  PubMed  Google Scholar 

  69. Soba P, Zhu S, Emoto K, Younger S, Yang SJ, Yu HH, Lee T, Jan LY, Jan YN (2007) Drosophila sensory neurons require Dscam for dendritic self-avoidance and proper dendritic field organization. Neuron 54(3):403–416. https://doi.org/10.1016/j.neuron.2007.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hattori D, Chen Y, Matthews BJ, Salwinski L, Sabatti C, Grueber WB, Zipursky SL (2009) Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature 461(7264):644–648. https://doi.org/10.1038/nature08431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wu W, Ahlsen G, Baker D, Shapiro L, Zipursky SL (2012) Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. Neuron 74(2):261–268

    Article  CAS  Google Scholar 

  72. Wang J, Zugates CT, Liang IH, Lee CHJ, Lee TM (2002) Drosophila Dscam is required for divergent segregation of sister branches and suppresses ectopic bifurcation of axons. Neuron 33(4):559–571. https://doi.org/10.1016/S0896-6273(02)00570-6

    Article  CAS  PubMed  Google Scholar 

  73. Wang J, Ma X, Yang JS, Zheng X, Zugates CT, Lee C-HJ, Lee T (2004) Transmembrane/juxtamembrane domain-dependent Dscam distribution and function during mushroom body neuronal morphogenesis. Neuron 43(5):663–672

    Article  CAS  Google Scholar 

  74. Zhu H, Hummel T, Clemens JC, Berdnik D, Zipursky SL, Luo L (2006) Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe. Nat Neurosci 9(3):349–355. https://doi.org/10.1038/nn1652

    Article  CAS  PubMed  Google Scholar 

  75. Lefebvre JL, Kostadinov D, Chen WV, Maniatis T, Sanes JR (2012) Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488(7412):517–521. https://doi.org/10.1038/nature11305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dascenco D, Erfurth ML, Izadifar A, Song M, Sachse S, Bortnick R, Urwyler O, Petrovic M, Ayaz D, He H, Kise Y, Thomas F, Kidd T, Schmucker D (2015) Slit and receptor tyrosine phosphatase 69D confer spatial specificity to axon branching via Dscam1. Cell 162(5):1140–1154. https://doi.org/10.1016/j.cell.2015.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Alavi M, Song M, King GL, Gillis T, Propst R, Lamanuzzi M, Bousum A, Miller A, Allen R, Kidd T (2016) Dscam1 forms a complex with Robo1 and the N-terminal fragment of Slit to promote the growth of longitudinal axons. PLoS Biol 14(9):e1002560. https://doi.org/10.1371/journal.pbio.1002560

    Article  PubMed  PubMed Central  Google Scholar 

  78. Petrovic M, Schmucker D (2015) Axonal wiring in neural development: target-independent mechanisms help to establish precision and complexity. BioEssays 37(9):996–1004. https://doi.org/10.1002/bies.201400222

    Article  PubMed  Google Scholar 

  79. Millard SS, Flanagan JJ, Pappu KS, Wu W, Zipursky SL (2007) Dscam2 mediates axonal tiling in the Drosophila visual system. Nature 447(7145):720

    Article  CAS  Google Scholar 

  80. Garrett AM, Khalil A, Walton DO, Burgess RW (2018) DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1809430115

    Article  PubMed  Google Scholar 

  81. Lee C, Kim N, Roy M, Graveley BR (2010) Massive expansions of Dscam splicing diversity via staggered homologous recombination during arthropod evolution. RNA 16(1):91–105. https://doi.org/10.1261/rna.1812710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by research grants from the National Natural Science Foundation of China (Grant nos. 31630089, 31430050, 91740104).

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Correspondence to Yongfeng Jin.

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Jin, Y., Li, H. Revisiting Dscam diversity: lessons from clustered protocadherins. Cell. Mol. Life Sci. 76, 667–680 (2019). https://doi.org/10.1007/s00018-018-2951-4

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