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Phylogenetic Analysis of the NEEP21/Calcyon/P19 Family of Endocytic Proteins: Evidence for Functional Evolution in the Vertebrate CNS

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Abstract

Endocytosis and vesicle trafficking are required for optimal neural transmission. Yet, little is currently known about the evolution of neuronal proteins regulating these processes. Here, we report the first phylogenetic study of NEEP21, calcyon, and P19, a family of neuronal proteins implicated in synaptic receptor endocytosis and recycling, as well as in membrane protein trafficking in the somatodendritic and axonal compartments of differentiated neurons. Database searches identified orthologs for P19 and NEEP21 in bony fish, but not urochordate or invertebrate phyla. Calcyon orthologs were only retrieved from mammalian databases and distant relatives from teleost fish. In situ localization of the P19 zebrafish ortholog, and extant progenitor of the gene family, revealed a CNS specific expression pattern. Based on non-synonymous nucleotide substitution rates, the calcyon genes appear to be under less intense negative selective pressure. Indeed, a functional group II WW domain binding motif was detected in primate and human calcyon, but not in non-primate orthologs. Sequencing of the calcyon gene from 80 human subjects revealed a non-synonymous single nucleotide polymorphism that abrogated group II WW domain protein binding. Altogether, our data indicate the NEEP21/calcyon/P19 gene family emerged, and underwent two rounds of gene duplication relatively late in metazoan evolution (but early in vertebrate evolution at the latest). As functional studies suggest NEEP21 and calcyon play related, but distinct roles in regulating vesicle trafficking at synapses, and in neurons in general, we propose the family arose in chordates to support a more diverse range of synaptic and behavioral responses.

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References

  • Alberi S, Boda B, Steiner P, Nikonenko I, Hirling H, Muller D (2005) The endosomal protein NEEP21 regulates AMPA receptor-mediated synaptic transmission and plasticity in the hippocampus. Mol Cell Neurosci 29:313–319

    Article  CAS  PubMed  Google Scholar 

  • Ali MK, Bergson C (2003) Elevated intracellular calcium triggers recruitment of the receptor cross-talk accessory protein calcyon to the plasma membrane. J Biol Chem 278:51654–51663

    Article  CAS  PubMed  Google Scholar 

  • Anisimova M, Liberles DA (2007) The quest for natural selection in the age of comparative genomics. Heredity 99:567–579

    Article  CAS  PubMed  Google Scholar 

  • Bai J, He F, Novikova SI, Undie AS, Dracheva S, Haroutunian V, Lidow MS (2004) Abnormalities in the dopamine system in schizophrenia may lie in altered levels of dopamine receptor-interacting proteins. Biol Psychiatry 56:427–440

    Article  CAS  PubMed  Google Scholar 

  • Baracskay KL, Haroutunian V, Meador-Woodruff JH (2006) Dopamine receptor signaling molecules are altered in elderly schizophrenic cortex. Synapse 60:271–279

    Article  CAS  PubMed  Google Scholar 

  • Bedford MT, Chan DC, Leder P (1997) FBP WW domains and the Abl SH3 domain bind to a specific class of proline-rich ligands. EMBO J 16:2376–2383

    Article  CAS  PubMed  Google Scholar 

  • Berglund-Sonnhammer AC, Steffansson P, Betts MJ, Liberles DA (2006) Optimal gene trees from sequences and species trees using a soft interpretation of parsimony. J Mol Evol 63:240–250

    Article  CAS  PubMed  Google Scholar 

  • Bredt DS, Nicoll RA (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40:361–379

    Article  CAS  PubMed  Google Scholar 

  • Clinton SM, Ibrahim HM, Frey KA, Davis KL, Haroutunian V, Meador-Woodruff JH (2005) Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin. Am J Psychiatry 162:1859–1871

    Article  PubMed  Google Scholar 

  • Dai R, Bergson C (2003) Structure and expression of the murine calcyon gene. Gene 311:111–117

    Article  CAS  PubMed  Google Scholar 

  • Davidson HT, Xiao J, Dai R, Bergson C (2009) Calcyon is necessary for activity-dependent AMPA receptor internalization and LTD in CA1 neurons of hippocampus 1. Eur J Neurosci 29:42–54

    Article  PubMed  Google Scholar 

  • Debaigt C, Hirling H, Steiner P, Vincent JP, Mazella J (2004) Crucial role of neuron-enriched endosomal protein of 21 kDa in sorting between degradation and recycling of internalized G-protein-coupled receptors. J Biol Chem 279:35687–35691

    Article  CAS  PubMed  Google Scholar 

  • Deborde S, Perret E, Gravotta D, Deora A, Salvarezza S, Schreiner R, Rodriguez-Boulan E (2008) Clathrin is a key regulator of basolateral polarity. Nature 452:719–723

    Article  CAS  PubMed  Google Scholar 

  • Dehal P, Boore JL (2005) Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol 3:e314

    Article  PubMed  Google Scholar 

  • Emes RD, Pocklington AJ, Anderson CN, Bayes A, Collins MO, Vickers CA, Croning MD, Malik BR, Choudhary JS, Armstrong JD, Grant SG (2008) Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat Neurosci 11:799–806

    Article  CAS  PubMed  Google Scholar 

  • Finn RD, Tate J, Mistry J, Coggill PC, Sammut SJ, Hotz HR, Ceric G, Forslund K, Eddy SR, Sonnhammer EL and Bateman A (2008) The Pfam protein families database. Nucleic Acids Res 36:D281–D288

    Article  CAS  PubMed  Google Scholar 

  • Gu X, Vander Velden K (2002) DIVERGE: phylogeny-based analysis for functional-structural divergence of a protein family. Bioinformatics 18:500–501

    Article  CAS  PubMed  Google Scholar 

  • Heynen AJ, Quinlan EM, Bae DC, Bear MF (2000) Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo. Neuron 28:527–536

    Article  CAS  PubMed  Google Scholar 

  • Hill RS, Walsh CA (2005) Molecular insights into human brain evolution. Nature 437:64–67

    Article  CAS  PubMed  Google Scholar 

  • Hughes T, Liberles DA (2007) The pattern of evolution of smaller-scale gene duplicates in mammalian genomes is more consistent with neo- than subfunctionalisation. J Mol Evol 65:574–588

    Article  CAS  PubMed  Google Scholar 

  • Hughes T, Liberles DA (2008) Whole-genome duplications in the ancestral vertebrate are detectable in the distribution of gene family sizes of tetrapod species. J Mol Evol 67:343–357

    Article  CAS  PubMed  Google Scholar 

  • Ilsley JL, Sudol M, Winder SJ (2002) The WW domain: linking cell signalling to the membrane cytoskeleton. Cell Signal 14:183–189

    Article  CAS  PubMed  Google Scholar 

  • Ingham RJ, Colwill K, Howard C, Dettwiler S, Lim CS, Yu J, Hersi K, Raaijmakers J, Gish G, Mbamalu G, Taylor L, Yeung B, Vassilovski G, Amin M, Chen F, Matskova L, Winberg G, Ernberg I, Linding R, O’donnell P, Starostine A, Keller W, Metalnikov P, Stark C, Pawson T (2005) WW domains provide a platform for the assembly of multiprotein networks. Mol Cell Biol 25:7092–7106

    Article  CAS  PubMed  Google Scholar 

  • Koh PO, Bergson C, Undie AS, Goldman-Rakic PS, Lidow MS (2003) Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia. Arch Gen Psychiatry 60:311–319

    Article  CAS  PubMed  Google Scholar 

  • Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948

    Article  CAS  PubMed  Google Scholar 

  • Laurin N, Misener VL, Crosbie J, Ickowicz A, Pathare T, Roberts W, Malone M, Tannock R, Schachar R, Kennedy JL, Barr CL (2005) Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder. Mol Psychiatry 10:1117–1125

    Article  CAS  PubMed  Google Scholar 

  • Liberles DA (2001) Evaluation of methods for determination of a reconstructed history of gene sequence evolution. Mol Biol Evol 18:2040–2047

    CAS  PubMed  Google Scholar 

  • Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126

    Article  CAS  PubMed  Google Scholar 

  • McCormack SG, Stornetta RL, Zhu JJ (2006) Synaptic AMPA receptor exchange maintains bidirectional plasticity. Neuron 50:75–88

    Article  CAS  PubMed  Google Scholar 

  • Nicholls RE, Alarcon JM, Malleret G, Carroll RC, Grody M, Vronskaya S, Kandel ER (2008) Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron 58:104–117

    Article  CAS  PubMed  Google Scholar 

  • Posada D, Crandall KA (1998) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817–818

    Article  CAS  PubMed  Google Scholar 

  • Roth MG (2008) Cell biology: porter and sorter. Nature 452:706–707

    Article  CAS  PubMed  Google Scholar 

  • Saberan-Djoneidi D, Marey-Semper I, Picart R, Studler JM, Tougard C, Glowinski J, Levi-Strauss M (1995) A 19-kDa protein belonging to a new family is expressed in the Golgi apparatus of neural cells. J Biol Chem 270:1888–1893

    Article  CAS  PubMed  Google Scholar 

  • Saberan-Djoneidi D, Picart R, Escalier D, Gelman M, Barret A, Tougard C, Glowinski J, Levi-Strauss M (1998) A 21-kDa polypeptide belonging to a new family of proteins is expressed in the Golgi apparatus of neural and germ cells. J Biol Chem 273:3909–3914

    Article  CAS  PubMed  Google Scholar 

  • Schmid EM, McMahon HT (2007) Integrating molecular and network biology to decode endocytosis. Nature 448:883–888

    Article  CAS  PubMed  Google Scholar 

  • Stamatakis A (2006) RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics 22:2688–2690

    Article  CAS  PubMed  Google Scholar 

  • Steiner P, Sarria JC, Glauser L, Magnin S, Catsicas S, Hirling H (2002) Modulation of receptor cycling by neuron-enriched endosomal protein of 21 kD. J Cell Biol 157:1197–1209

    Article  CAS  PubMed  Google Scholar 

  • Steiner P, Alberi S, Kulangara K, Yersin A, Sarria JC, Regulier E, Kasas S, Dietler G, Muller D, Catsicas S, Hirling H (2005) Interactions between NEEP21, GRIP1 and GluR2 regulate sorting and recycling of the glutamate receptor subunit GluR2. EMBO J 24:2873–2884

    Article  CAS  PubMed  Google Scholar 

  • Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547

    Article  PubMed  Google Scholar 

  • Teyler TJ, Discenna P (1984) Long-term potentiation as a candidate mnemonic device. Brain Res 319:15–28

    CAS  PubMed  Google Scholar 

  • Thisse C, Thisse B, Schilling TF, Postlethwait JH (1993) Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos. Development 119:1203–1215

    CAS  PubMed  Google Scholar 

  • von Bartheld CS (2004) Axonal transport and neuronal transcytosis of trophic factors, tracers, and pathogens 3. J Neurobiol 58:295–314

    Article  Google Scholar 

  • Wang HY, Chien HC, Osada N, Hashimoto K, Sugano S, Gojobori T, Chou CK, Tsai SF, Wu CI, Shen CK (2007) Rate of evolution in brain-expressed genes in humans and other primates. PLoS Biol 5:e13

    Article  PubMed  Google Scholar 

  • Westerfield M (1995) The Zebrafish Book: a guide for the laboratory use of zebrafish (Brachydanio rerio). University of Oregon Press, Eugene, OR

    Google Scholar 

  • White R, Gonsior C, Kramer-Albers EM, Stohr N, Huttelmaier S, Trotter J (2008) Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules. J Cell Biol 181:579–586

    Article  CAS  PubMed  Google Scholar 

  • Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097

    Article  CAS  PubMed  Google Scholar 

  • Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y, Chowdari KV, Cardno AG, Zammit S, Jones LA, Murphy KC, Sanders RD, McCarthy G, Gray MY, Jones G, Holmans P, Nimgaonkar V, Adolfson R, Osby U, Terenius L, Sedvall G, O’Donovan MC, Owen MJ (2003) A systematic genome wide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 73:1355–1367

    Article  CAS  PubMed  Google Scholar 

  • Xiao J, Dai R, Negyessy L, Bergson C (2006) Calcyon, a novel partner of clathrin light chain, stimulates clathrin-mediated endocytosis. J Biol Chem 281:15182–15193

    Article  CAS  PubMed  Google Scholar 

  • Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood 1. Mol Biol Evol 24:1586–1591

    Article  CAS  PubMed  Google Scholar 

  • Yap CC, Wisco D, Kujala P, Lasiecka ZM, Cannon JT, Chang MC, Hirling H, Klumperman J, Winckler B (2008) The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM. J Cell Biol 180:827–842

    Article  CAS  PubMed  Google Scholar 

  • Zelenin S, Aperia A, Diaz HR (2002) Calcyon in the rat brain: cloning of cDNA and expression of mRNA. J Comp Neurol 446:37–45

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the NIH MH063271 (C.B.). This work was also funded by an institutional NIH-INBRE award to University of Wyoming and by NSF award 0743374 (DAL). We thank Haiqin Jin for her excellent technical support.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA, 30912-2300, USA

    Nagendran Muthusamy & Clare Bergson

  2. Department of Molecular Biology, University of Wyoming, Laramie, WY, USA

    Sanaa A. Ahmed & David A. Liberles

  3. Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA

    Brinda K. Rana

  4. Department of Cell Biology and Institute of Molecular Genetics, Medical College of Georgia, Augusta, GA, USA

    Sammy Navarre & David J. Kozlowski

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  1. Nagendran Muthusamy
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Correspondence to Clare Bergson.

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Muthusamy, N., Ahmed, S.A., Rana, B.K. et al. Phylogenetic Analysis of the NEEP21/Calcyon/P19 Family of Endocytic Proteins: Evidence for Functional Evolution in the Vertebrate CNS. J Mol Evol 69, 319–332 (2009). https://doi.org/10.1007/s00239-009-9273-y

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