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. 2011 Sep 9;2(8):647–655. doi: 10.1007/s13238-011-1072-8

Dscam mutation leads to hydrocephalus and decreased motor function

Yiliang Xu 1, Haihong Ye 2,✉, Yan Shen 1, Qi Xu 1,✉, Li Zhu 2, Jianghong Liu 2, Jane Y Wu 2,3,✉
PMCID: PMC3893070  NIHMSID: NIHMS492403  PMID: 21904980

Abstract

The nervous system is one of the most complicated organ systems in invertebrates and vertebrates. Down syndrome cell adhesion molecule (DSCAM) of the immunoglobulin (Ig) superfamily is expressed widely in the nervous system during embryonic development. Previous studies in Drosophila suggest that Dscam plays important roles in neural development including axon branching, dendritic tiling and cell spacing. However, the function of the mammalian DSCAM gene in the formation of the nervous system remains unclear. Here, we show that Dscamdel17 mutant mice exhibit severe hydrocephalus, decreased motor function and impaired motor learning ability. Our data indicate that the mammalian DSCAM gene is critical for the formation of the central nervous system.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-011-1072-8 and is accessible for authorized users.

Keywords: Down syndrome cell adhesion molecule, motor function, motor learning, hydrocephalus

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Footnotes

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-011-1072-8 and is accessible for authorized users.

Contributor Information

Haihong Ye, Email: yehaihong@gmail.com.

Qi Xu, Email: qixuangela@gmail.com.

Jane Y. Wu, Email: jane-wu@northwestern.edu

References

  1. Agarwala K.L., Ganesh S., Suzuki T., Akagi T., Kaneko K., Amano K., Tsutsumi Y., Yamaguchi K., Hashikawa T., Yamakawa K. Dscam is associated with axonal and dendritic features of neuronal cells. J Neurosci Res. 2001;66:337–346. doi: 10.1002/jnr.1226. [DOI] [PubMed] [Google Scholar]
  2. Agarwala K.L., Nakamura S., Tsutsumi Y., Yamakawa K. Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion. Brain Res Mol Brain Res. 2000;79:118–126. doi: 10.1016/S0169-328X(00)00108-X. [DOI] [PubMed] [Google Scholar]
  3. Amano K., Fujii M., Arata S., Tojima T., Ogawa M., Morita N., Shimohata A., Furuichi T., Itohara S., Kamiguchi H., et al. DSCAM deficiency causes loss of pre-inspiratory neuron synchroneity and perinatal death. J Neurosci. 2009;29:2984–2996. doi: 10.1523/JNEUROSCI.3624-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barlow G.M., Lyons G.E., Richardson J.A., Sarnat H.B., Korenberg J.R. DSCAM: an endogenous promoter drives expression in the developing CNS and neural crest. Biochem Biophys Res Commun. 2002;299:1–6. doi: 10.1016/S0006-291X(02)02548-2. [DOI] [PubMed] [Google Scholar]
  5. Barlow G.M., Micales B., Chen X.N., Lyons G.E., Korenberg J. R. Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum? Biochem Biophys Res Commun. 2002;293:881–891. doi: 10.1016/S0006-291X(02)00307-8. [DOI] [PubMed] [Google Scholar]
  6. Basel-Vanagaite L., Straussberg R., Friez M.J., Inbar D., Korenreich L., Shohat M., Schwartz C.E. Expanding the phenotypic spectrum of L1CAM-associated disease. Clin Genet. 2006;69:414–419. doi: 10.1111/j.1399-0004.2006.00607.x. [DOI] [PubMed] [Google Scholar]
  7. Bertolin C., Boaretto F., Barbon G., Salviati L., Lapi E., Divizia M. T., Garavelli L., Occhi G., Vazza G., Mostacciuolo M.L. Novel mutations in the L1CAM gene support the complexity of L1 syndrome. J Neurol Sci. 2010;294:124–126. doi: 10.1016/j.jns.2010.03.030. [DOI] [PubMed] [Google Scholar]
  8. Brites D., McTaggart S., Morris K., Anderson J., Thomas K., Colson I., Fabbro T., Little T.J., Ebert D., Du Pasquier L. The Dscam homologue of the crustacean Daphnia is diversified by alternative splicing like in insects. Mol Biol Evol. 2008;25:1429–1439. doi: 10.1093/molbev/msn087. [DOI] [PubMed] [Google Scholar]
  9. Del Bigio M.R. Ependymal cells: biology and pathology. Acta Neuropathol. 2010;119:55–73. doi: 10.1007/s00401-009-0624-y. [DOI] [PubMed] [Google Scholar]
  10. Frankin K.B.J., Paxinos G. The mouse brain in stereotaxic coordinates. New York: Academic; 1997. [Google Scholar]
  11. Fuerst P.G., Bruce F., Tian M., Wei W., Elstrott J., Feller M.B., Erskine L., Singer J.H., Burgess R.W. DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina. Neuron. 2009;64:484–497. doi: 10.1016/j.neuron.2009.09.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuerst P.G., Koizumi A., Masland R.H., Burgess R.W. Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature. 2008;451:470–474. doi: 10.1038/nature06514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hattori D., Demir E., Kim H.W., Viragh E., Zipursky S.L., Dickson B.J. Dscam diversity is essential for neuronal wiring and self-recognition. Nature. 2007;449:223–227. doi: 10.1038/nature06099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haverkamp F., Wölfle J., Aretz M., Krämer A., Höhmann B., Fahnenstich H., Zerres K. Congenital hydrocephalus internus and aqueduct stenosis: aetiology and implications for genetic counselling. Eur J Pediatr. 1999;158:474–478. doi: 10.1007/s004310051123. [DOI] [PubMed] [Google Scholar]
  15. Hughes M.E., Bortnick R., Tsubouchi A., Bäumer P., Kondo M., Uemura T., Schmucker D. Homophilic Dscam interactions control complex dendrite morphogenesis. Neuron. 2007;54:417–427. doi: 10.1016/j.neuron.2007.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hummel T., Vasconcelos M.L., Clemens J.C., Fishilevich Y., Vosshall L.B., Zipursky S.L. Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron. 2003;37:221–231. doi: 10.1016/S0896-6273(02)01183-2. [DOI] [PubMed] [Google Scholar]
  17. Jackson S.R., Guner Y.S., Woo R., Randolph L.M., Ford H., Shin C.E. L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung’s disease. Pediatr Surg Int. 2009;25:823–825. doi: 10.1007/s00383-009-2420-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jones B.J., Roberts D.J. The quantiative measurement of motor inco-ordination in naive mice using an acelerating rotarod. J Pharm Pharmacol. 1968;20:302–304. doi: 10.1111/j.2042-7158.1968.tb09743.x. [DOI] [PubMed] [Google Scholar]
  19. Jouet M., Rosenthal A., MacFarlane J., Kenwrick S., Donnai D. A missense mutation confirms the L1 defect in X-linked hydrocephalus (HSAS) Nat Genet. 1993;4:331. doi: 10.1038/ng0893-331. [DOI] [PubMed] [Google Scholar]
  20. Liebau M.C., Gal A., Superti-Furga A., Omran H., Pohl M. L1CAM mutation in a boy with hydrocephalus and duplex kidneys. Pediatr Nephrol. 2007;22:1058–1061. doi: 10.1007/s00467-006-0424-8. [DOI] [PubMed] [Google Scholar]
  21. Liu G., Li W., Wang L., Kar A., Guan K.L., Rao Y., Wu J.Y. DSCAM functions as a netrin receptor in commissural axon pathfinding. Proc Natl Acad Sci U S A. 2009;106:2951–2956. doi: 10.1073/pnas.0811083106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ly A., Nikolaev A., Suresh G., Zheng Y., Tessier-Lavigne M., Stein E. DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1. Cell. 2008;133:1241–1254. doi: 10.1016/j.cell.2008.05.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matthews B.J., Kim M.E., Flanagan J.J., Hattori D., Clemens J.C., Zipursky S.L., Grueber W.B. Dendrite self-avoidance is controlled by Dscam. Cell. 2007;129:593–604. doi: 10.1016/j.cell.2007.04.013. [DOI] [PubMed] [Google Scholar]
  24. Meijers R., Puettmann-Holgado R., Skiniotis G., Liu J.H., Walz T., Wang J.H., Schmucker D. Structural basis of Dscam isoform specificity. Nature. 2007;449:487–491. doi: 10.1038/nature06147. [DOI] [PubMed] [Google Scholar]
  25. Nakamura Y., Lee S., Haddox C.L., Weaver E.J., Lemmon V.P. Role of the cytoplasmic domain of the L1 cell adhesion molecule in brain development. J Comp Neurol. 2010;518:1113–1132. doi: 10.1002/cne.22267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schäfer M.K., Altevogt P. L1CAM malfunction in the nervous system and human carcinomas. Cell Mol Life Sci. 2010;67:2425–2437. doi: 10.1007/s00018-010-0339-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schmucker D., Clemens J.C., Shu H., Worby C.A., Xiao J., Muda M., Dixon J.E., Zipursky S.L. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell. 2000;101:671–684. doi: 10.1016/S0092-8674(00)80878-8. [DOI] [PubMed] [Google Scholar]
  28. Soba P., Zhu S., Emoto K., Younger S., Yang S.J., Yu H.H., Lee T., Jan L.Y., Jan Y.N. Drosophila sensory neurons require Dscam for dendritic self-avoidance and proper dendritic field organization. Neuron. 2007;54:403–416. doi: 10.1016/j.neuron.2007.03.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tapanes-Castillo A., Weaver E.J., Smith R.P., Kamei Y., Caspary T., Hamilton-Nelson K.L., Slifer S.H., Martin E.R., Bixby J.L., Lemmon V.P. A modifier locus on chromosome 5 contributes to L1 cell adhesion molecule X-linked hydrocephalus in mice. Neurogenetics. 2010;11:53–71. doi: 10.1007/s10048-009-0203-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vos Y.J., Hofstra R.M. An updated and upgraded L1CAM mutation database. Hum Mutat. 2010;31:E1102–E1109. doi: 10.1002/humu.21172. [DOI] [PubMed] [Google Scholar]
  31. Wang J., Zugates C.T., Liang I.H., Lee C.H., Lee T. Drosophila Dscam is required for divergent segregation of sister branches and suppresses ectopic bifurcation of axons. Neuron. 2002;33:559–571. doi: 10.1016/S0896-6273(02)00570-6. [DOI] [PubMed] [Google Scholar]
  32. Wilson P.L., Kattman B.B., Mulvihill J.J., Li S., Wilkins J., Wagner A.F., Goodman J.R. Prenatal identification of a novel R937P L1CAM missense mutation. Genet Test Mol Biomarkers. 2009;13:515–519. doi: 10.1089/gtmb.2009.0017. [DOI] [PubMed] [Google Scholar]
  33. Wojtowicz W.M., Flanagan J.J., Millard S.S., Zipursky S.L., Clemens J.C. Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding. Cell. 2004;118:619–633. doi: 10.1016/j.cell.2004.08.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wojtowicz W.M., Wu W., Andre I., Qian B., Baker D., Zipursky S.L. A vast repertoire of Dscam binding specificities arises from modular interactions of variable Ig domains. Cell. 2007;130:1134–1145. doi: 10.1016/j.cell.2007.08.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yamagata M., Sanes J.R. Synaptic localization and function of Sidekick recognition molecules require MAGI scaffolding proteins. J Neurosci. 2010;30:3579–3588. doi: 10.1523/JNEUROSCI.6319-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yamakawa K., Huot Y.K., Haendelt M.A., Hubert R., Chen X.N., Lyons G.E., Korenberg J.R. 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. 1998;7:227–237. doi: 10.1093/hmg/7.2.227. [DOI] [PubMed] [Google Scholar]
  37. Zhang J., Williams M.A., Rigamonti D. Genetics of human hydrocephalus. J Neurol. 2006;253:1255–1266. doi: 10.1007/s00415-006-0245-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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