1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Cell and Developmental Biology
  4. Volume 34, 2018
  5. Article

Annual Review of Cell and Developmental Biology

Volume 34, 2018

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Abstract

The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.

Keyword(s): homophilic interactions, neural circuits, neuropsychiatric diseases, protocadherins, self-avoidance, single-neuron identity, stochastic expression, tiling
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-100616-060701
2018-10-06
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/34/1/annurev-cellbio-100616-060701.html?itemId=/content/journals/10.1146/annurev-cellbio-100616-060701&mimeType=html&fmt=ahah

Literature Cited

  1. Bargmann CI, Newsome WT 2014. The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative and neurology. JAMA Neurol 71:675–76
     [Google Scholar]
  2. Bates M, Jones SA, Zhuang X 2013. Stochastic optical reconstruction microscopy (STORM): a method for superresolution fluorescence imaging. Cold Spring Harb. Protoc. 2013:498–520
     [Google Scholar]
  3. Berger M, Gray JA, Roth BL 2009. The expanded biology of serotonin. Annu. Rev. Med. 60:355–66
     [Google Scholar]
  4. Bressel OC, Khan M, Mombaerts P 2016. Linear correlation between the number of olfactory sensory neurons expressing a given mouse odorant receptor gene and the total volume of the corresponding glomeruli in the olfactory bulb. J. Comp. Neurol. 524:199–209
     [Google Scholar]
  5. Buchanan SM, Schalm SS, Maniatis T 2010. Proteolytic processing of protocadherin proteins requires endocytosis. PNAS 107:17774–79
     [Google Scholar]
  6. Cai D, Cohen KB, Luo T, Lichtman JW, Sanes JR 2013. Improved tools for the Brainbow toolbox. Nat. Methods 10:540–47
     [Google Scholar]
  7. Chen K, Hu J, Moore DL, Liu R, Kessans SA et al. 2015. Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. PNAS 112:E3535–44
     [Google Scholar]
  8. Chen WV, Alvarez FJ, Lefebvre JL, Friedman B, Nwakeze C et al. 2012. Functional significance of isoform diversification in the protocadherin gamma gene cluster. Neuron 75:402–9
     [Google Scholar]
  9. Chen WV, Maniatis T 2013. Clustered protocadherins. Development 140:3297–302
     [Google Scholar]
  10. Chen WV, Nwakeze CL, Denny CA, O'Keeffe S, Rieger MA et al. 2017. Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science 356:406–11
     [Google Scholar]
  11. Chung K, Deisseroth K 2013. CLARITY for mapping the nervous system. Nat. Methods 10:508–13
     [Google Scholar]
  12. Daubert EA, Condron BG 2010. Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33:424–34
     [Google Scholar]
  13. El Hajj N, Dittrich M, Haaf T 2017. Epigenetic dysregulation of protocadherins in human disease. Semin. Cell Dev. Biol. 69:172–82
     [Google Scholar]
  14. Espinosa JS, Tea JS, Luo L 2014. Mosaic analysis with double markers (MADM) in mice. Cold Spring Harb. Protoc. 2014:182–89
     [Google Scholar]
  15. Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A et al. 2005. Monoallelic yet combinatorial expression of variable exons of the protocadherin-α gene cluster in single neurons. Nat. Genet. 37:171–76
     [Google Scholar]
  16. Garrett AM, Schreiner D, Lobas MA, Weiner JA 2012. γ-Protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. Neuron 74:269–76
     [Google Scholar]
  17. Golan-Mashiach M, Grunspan M, Emmanuel R, Gibbs-Bar L, Dikstein R, Shapiro E 2012. Identification of CTCF as a master regulator of the clustered protocadherin genes. Nucleic Acids Res 40:3378–91
     [Google Scholar]
  18. Goodman KM, Rubinstein R, Dan H, Bahna F, Mannepalli S et al. 2017. Protocadherin cis-dimer architecture and recognition unit diversity. PNAS 114:E9829–37
     [Google Scholar]
  19. Goodman KM, Rubinstein R, Thu CA, Bahna F, Mannepalli S et al. 2016.a Structural basis of diverse homophilic recognition by clustered α- and β-protocadherins. Neuron 90:709–23
     [Google Scholar]
  20. Goodman KM, Rubinstein R, Thu CA, Mannepalli S, Bahna F et al. 2016.b γ-Protocadherin structural diversity and functional implications. eLife 5:e20930
     [Google Scholar]
  21. Guo Y, Monahan K, Wu H, Gertz J, Varley KE et al. 2012. CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice. PNAS 109:21081–86
     [Google Scholar]
  22. Guo Y, Xu Q, Canzio D, Shou J, Li J et al. 2015. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162:900–10
     [Google Scholar]
  23. Han MH, Lin C, Meng S, Wang X 2010. Proteomics analysis reveals overlapping functions of clustered protocadherins. Mol. Cell. Proteom. 9:71–83
     [Google Scholar]
  24. Hasegawa S, Hamada S, Kumode Y, Esumi S, Katori S et al. 2008. The protocadherin-α family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse. Mol. Cell. Neurosci. 38:66–79
     [Google Scholar]
  25. Hasegawa S, Kobayashi H, Kumagai M, Nishimaru H, Tarusawa E et al. 2017. Clustered protocadherins are required for building functional neural circuits. Front. Mol. Neurosci. 10:114
     [Google Scholar]
  26. Hasegawa S, Kumagai M, Hagihara M, Nishimaru H, Hirano K et al. 2016. Distinct and cooperative functions for the protocadherin-α, -β and -γ clusters in neuronal survival and axon targeting. Front. Mol. Neurosci. 9:155
     [Google Scholar]
  27. Hattori D, Millard SS, Wojtowicz WM, Zipursky SL 2008. Dscam-mediated cell recognition regulates neural circuit formation. Annu. Rev. Cell Dev. Biol. 24:597–620
     [Google Scholar]
  28. Hirabayashi T, Yagi T 2014. Protocadherins in neurological diseases. Adv. Neurobiol. 8:293–314
     [Google Scholar]
  29. Hirano K, Kaneko R, Izawa T, Kawaguchi M, Kitsukawa T, Yagi T 2012. Single-neuron diversity generated by Protocadherin-β cluster in mouse central and peripheral nervous systems. Front. Mol. Neurosci. 5:90
     [Google Scholar]
  30. Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T 2012. CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep 2:345–57
     [Google Scholar]
  31. Hirayama T, Yagi T 2017. Regulation of clustered protocadherin genes in individual neurons. Semin. Cell Dev. Biol. 69:122–30
     [Google Scholar]
  32. 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 37:221–31
     [Google Scholar]
  33. Ing-Esteves S, Kostadinov D, Marocha J, Sing AD, Joseph KS et al. 2018. Combinatorial effects of alpha- and gamma-protocadherins on neuronal survival and dendritic self-avoidance. J. Neurosci. 38:2713–29
     [Google Scholar]
  34. Isbel L, Prokopuk L, Wu H, Daxinger L, Oey H et al. 2016. Wiz binds active promoters and CTCF-binding sites and is required for normal behaviour in the mouse. eLife 5:e15082
     [Google Scholar]
  35. Jacobs BL, Azmitia EC 1992. Structure and function of the brain serotonin system. Physiol. Rev. 72:165–229
     [Google Scholar]
  36. Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W et al. 2017. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat. Genet. 49:1239–50
     [Google Scholar]
  37. Kai N, Mishina M, Yagi T 1997. Molecular cloning of Fyn-associated molecules in the mouse central nervous system. J. Neurosci. Res. 48:407–24
     [Google Scholar]
  38. Kaneko R, Kato H, Kawamura Y, Esumi S, Hirayama T et al. 2006. Allelic gene regulation of Pcdh-α and Pcdh-γ clusters involving both monoallelic and biallelic expression in single Purkinje cells. J. Biol. Chem. 281:30551–60
     [Google Scholar]
  39. Katori S, Hamada S, Noguchi Y, Fukuda E, Yamamoto T et al. 2009. Protocadherin-α family is required for serotonergic projections to appropriately innervate target brain areas. J. Neurosci. 29:9137–47
     [Google Scholar]
  40. Katori S, Noguchi-Katori Y, Okayama A, Kawamura Y, Luo W et al. 2017. Protocadherin-αC2 is required for diffuse projections of serotonergic axons. Sci. Rep. 7:15908
     [Google Scholar]
  41. Kawaguchi M, Toyama T, Kaneko R, Hirayama T, Kawamura Y, Yagi T 2008. Relationship between DNA methylation states and transcription of individual isoforms encoded by the protocadherin-α gene cluster. J. Biol. Chem. 283:12064–75
     [Google Scholar]
  42. Kehayova P, Monahan K, Chen W, Maniatis T 2011. Regulatory elements required for the activation and repression of the protocadherin-α gene cluster. PNAS 108:17195–200
     [Google Scholar]
  43. Kiyasova V, Gaspar P 2011. Development of raphe serotonin neurons from specification to guidance. Eur. J. Neurosci. 34:1553–62
     [Google Scholar]
  44. Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R et al. 1998. Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex. Neuron 20:1137–51
     [Google Scholar]
  45. Kostadinov D, Sanes JR 2015. Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function. eLife 4:e08964
     [Google Scholar]
  46. Ledderose J, Dieter S, Schwarz MK 2013. Maturation of postnatally generated olfactory bulb granule cells depends on functional γ-protocadherin expression. Sci. Rep. 3:1514
     [Google Scholar]
  47. Lefebvre JL 2017. Neuronal territory formation by the atypical cadherins and clustered protocadherins. Semin. Cell Dev. Biol. 69:111–21
     [Google Scholar]
  48. Lefebvre JL, Kostadinov D, Chen WV, Maniatis T, Sanes JR 2012. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488:517–21
     [Google Scholar]
  49. Lefebvre JL, Zhang Y, Meister M, Wang X, Sanes JR 2008. γ-Protocadherins regulate neuronal survival but are dispensable for circuit formation in retina. Development 135:4141–51
     [Google Scholar]
  50. Li SA, Cheng L, Yu Y, Chen Q 2016. Structural basis of Dscam1 homodimerization: insights into context constraint for protein recognition. Sci. Adv. 2:e1501118
     [Google Scholar]
  51. Mah KM, Weiner JA 2017. Regulation of Wnt signaling by protocadherins. Semin. Cell Dev. Biol. 69:158–71
     [Google Scholar]
  52. Maiuri P, Knezevich A, De Marco A, Mazza D, Kula A et al. 2011. Fast transcription rates of RNA polymerase II in human cells. EMBO Rep 12:1280–85
     [Google Scholar]
  53. Mason AG, Slieker RC, Balog J, Lemmers R, Wong CJ et al. 2017. SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skelet. Muscle 7:12
     [Google Scholar]
  54. Mombaerts P, Wang F, Dulac C, Chao SK, Nemes A et al. 1996. Visualizing an olfactory sensory map. Cell 87:675–86
     [Google Scholar]
  55. Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM et al. 2012. Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-α gene expression. PNAS 109:9125–30
     [Google Scholar]
  56. Mountoufaris G, Chen WV, Hirabayashi Y, O'Keeffe S, Chevee M et al. 2017. Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly. Science 356:411–14
     [Google Scholar]
  57. Murata Y, Hamada S, Morishita H, Mutoh T, Yagi T 2004. Interaction with protocadherin-γ regulates the cell surface expression of protocadherin-α. J. Biol. Chem. 279:49508–16
     [Google Scholar]
  58. Nicoludis JM, Lau SY, Scharfe CP, Marks DS, Weihofen WA, Gaudet R 2015. Structure and sequence analyses of clustered protocadherins reveal antiparallel interactions that mediate homophilic specificity. Structure 23:2087–98
     [Google Scholar]
  59. 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
     [Google Scholar]
  60. Noonan JP, Grimwood J, Schmutz J, Dickson M, Myers RM 2004. Gene conversion and the evolution of protocadherin gene cluster diversity. Genome Res 14:354–66
     [Google Scholar]
  61. Olivier B 2015. Serotonin: a never-ending story. Eur. J. Pharmacol. 753:2–18
     [Google Scholar]
  62. Peek SL, Mah KM, Weiner JA 2017. Regulation of neural circuit formation by protocadherins. Cell. Mol. Life Sci. 74:4133–57
     [Google Scholar]
  63. Phillips GR, LaMassa N, Nie YM 2017. Clustered protocadherin trafficking. Semin. Cell Dev. Biol. 69:131–39
     [Google Scholar]
  64. Prasad T, Wang X, Gray PA, Weiner JA 2008. A differential developmental pattern of spinal interneuron apoptosis during synaptogenesis: insights from genetic analyses of the protocadherin-γ gene cluster. Development 135:4153–64
     [Google Scholar]
  65. Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID et al. 2014. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:1665–80
     [Google Scholar]
  66. Regev A, Teichmann SA, Lander ES, Amit I, Benoist C et al. 2017. The Human Cell Atlas. eLife 6:e27041
     [Google Scholar]
  67. Renier N, Wu Z, Simon DJ, Yang J, Ariel P, Tessier-Lavigne M 2014. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159:896–910
     [Google Scholar]
  68. Ribich S, Tasic B, Maniatis T 2006. Identification of long-range regulatory elements in the protocadherin-α gene cluster. PNAS 103:19719–24
     [Google Scholar]
  69. Rubinstein R, Goodman KM, Maniatis T, Shapiro L, Honig B 2017. Structural origins of clustered protocadherin-mediated neuronal barcoding. Semin. Cell Dev. Biol. 69:140–50
     [Google Scholar]
  70. Rubinstein R, Thu CA, Goodman KM, Wolcott HN, Bahna F et al. 2015. Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell 163:629–42
     [Google Scholar]
  71. Sano K, Tanihara H, Heimark RL, Obata S, Davidson M et al. 1993. Protocadherins: a large family of cadherin-related molecules in central nervous system. EMBO J 12:2249–56
     [Google Scholar]
  72. Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Maniatis T 2010. Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret. PNAS 107:13894–99
     [Google Scholar]
  73. Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J et al. 2000. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101:671–84
     [Google Scholar]
  74. Schreiner D, Weiner JA 2010. Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion. PNAS 107:14893–98
     [Google Scholar]
  75. Suo L, Lu H, Ying G, Capecchi MR, Wu Q 2012. Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. J. Mol. Cell Biol. 4:362–76
     [Google Scholar]
  76. Suzuki ST 1996. Structural and functional diversity of cadherin superfamily: are new members of cadherin superfamily involved in signal transduction pathway. ? J. Cell. Biochem. 61:531–42
     [Google Scholar]
  77. Takeuchi H, Sakano H 2014. Neural map formation in the mouse olfactory system. Cell. Mol. Life Sci. 71:3049–57
     [Google Scholar]
  78. Tarusawa E, Sanbo M, Okayama A, Miyashita T, Kitsukawa T et al. 2016. Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins. BMC Biol 14:103
     [Google Scholar]
  79. Tasic B, Nabholz CE, Baldwin KK, Kim Y, Rueckert EH et al. 2002. Promoter choice determines splice site selection in protocadherin α and γ pre-mRNA splicing. Mol. Cell 10:21–33
     [Google Scholar]
  80. Thu CA, Chen WV, Rubinstein R, Chevee M, Wolcott HN et al. 2014. Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins. Cell 158:1045–59
     [Google Scholar]
  81. Toyoda S, Kawaguchi M, Kobayashi T, Tarusawa E, Toyama T et al. 2014. Developmental epigenetic modification regulates stochastic expression of clustered protocadherin genes, generating single neuron diversity. Neuron 82:94–108
     [Google Scholar]
  82. Wang X, Su H, Bradley A 2002.a Molecular mechanisms governing Pcdh-γ gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev 16:1890–905
     [Google Scholar]
  83. Wang X, Weiner JA, Levi S, Craig AM, Bradley A, Sanes JR 2002.b Gamma protocadherins are required for survival of spinal interneurons. Neuron 36:843–54
     [Google Scholar]
  84. Weiner JA, Wang X, Tapia JC, Sanes JR 2005. Gamma protocadherins are required for synaptic development in the spinal cord. PNAS 102:8–14
     [Google Scholar]
  85. 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 118:619–33
     [Google Scholar]
  86. 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 130:1134–45
     [Google Scholar]
  87. Wu Q, Maniatis T 1999. A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97:779–90
     [Google Scholar]
  88. Wu Q, Zhang T, Cheng JF, Kim Y, Grimwood J et al. 2001. Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res 11:389–404
     [Google Scholar]
  89. Yagi T 2008. Clustered protocadherin family. Dev. Growth Differ. 50:Suppl. 1131–40
     [Google Scholar]
  90. Yin M, Wang J, Wang M, Li X, Zhang M et al. 2017. Molecular mechanism of directional CTCF recognition of a diverse range of genomic sites. Cell Res 27:1365–77
     [Google Scholar]
  91. Yokota S, Hirayama T, Hirano K, Kaneko R, Toyoda S et al. 2011. Identification of the cluster control region for the protocadherin-β genes located beyond the protocadherin-γ cluster. J. Biol. Chem. 286:31885–95
     [Google Scholar]
  92. Yu WP, Rajasegaran V, Yew K, Loh WL, Tay BH et al. 2008. Elephant shark sequence reveals unique insights into the evolutionary history of vertebrate genes: a comparative analysis of the protocadherin cluster. PNAS 105:3819–24
     [Google Scholar]
  93. 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
     [Google Scholar]
  94. 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. 9:349–55
     [Google Scholar]
  95. Zipursky SL, Grueber WB 2013. The molecular basis of self-avoidance. Annu. Rev. Neurosci. 36:547–68
     [Google Scholar]
/content/journals/10.1146/annurev-cellbio-100616-060701
Loading
Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly
Annual Review of Cell and Developmental Biology 34, 471 (2018); https://doi.org/10.1146/annurev-cellbio-100616-060701
/content/journals/10.1146/annurev-cellbio-100616-060701
/content/journals/10.1146/annurev-cellbio-100616-060701
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error