Journal Mobile Options
Table of Contents
Vol. 27, No. 6, 2005
Issue release date: 2005
Dev Neurosci 2005;27:378–396

Immunohistochemical and Microarray Analyses of a Mouse Model for the Smith-Lemli-Opitz Syndrome

Waage-Baudet H. · Dunty Jr. W.C. · Dehart D.B. · Hiller S. · Sulik K.K.
Departments of aCell and Developmental Biology, bPathology, cBowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, N.C., and dCancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, Md., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3β-hydroxysteroid-Δ7-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7–/–) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7–/–, Dhcr7+/– and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7–/– hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7–/– mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Barallobre MJ, Del Rio JA, Alcantara S, Borrell V, Aguado F, Ruiz M, Carmona MA, Martin M, Fabre M, Yuste R, Tessier-Lavigne M, Soriano E (2000): Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice. Development 127:4797–4810.
  2. Becher A, Drenckhahn A, Pahner I, Ahnert-Hilger G (1999): The synaptophysin-synaptobrevin complex is developmentally upregulated in cultivated neurons but is absent in neuroendocrine cells. Eur J Cell Biol 78:650–656.
  3. Becker EB, Bonni A (2004): Cell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol 72:1–25.
  4. Bjorkhem I, Starck L, Andersson U, Lutjohann D, von Bahr S, Pikuleva I, Babiker A, Diczfalusy U (2001): Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S- and 27-hydroxycholesterol. J Lipid Res 42:366–371.
  5. Brown MS, Goldstein JL (1997): The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340.
  6. Brown MS, Goldstein JL (1999): A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96:11041–11048.
  7. Cadigan KM, Nusse R (1997): Wnt signaling: a common theme in animal development. Genes Dev 11:3286–3305.
  8. Caldas H, Herman GE (2003): NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. Hum Mol Genet 12:2981–2991.
  9. Carrasco J, Penkowa M, Hadberg H, Molinero A, Hidalgo J (2000): Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice. Eur J Neurosci 12:2311–2322.
  10. Chamberlain LH, Gould GW (2002): The vesicle- and target-SNARE proteins that mediate Glut4 vesicle fusion are localized in detergent-insoluble lipid rafts present on distinct intracellular membranes. J Biol Chem 277:49750–49754.
  11. Charron F, Stein E, Jeong J, McMahon AP, Tessier-Lavigne M (2003): The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113:11–23.
  12. Chen D, Xu W, Bales E, Colmenares C, Conacci-Sorrell M, Ishii S, Stavnezer E, Campisi J, Fisher DE, Ben Ze’ev A, Medrano EE (2003): SKI activates Wnt/beta-catenin signaling in human melanoma. Cancer Res 63:6626–6634.
  13. Chung RS, Vickers JC, Chuah MI, West AK (2003): Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury. J Neurosci 23:3336–3342.
  14. Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H, Sicinski P (2002): Development of mice expressing a single D-type cyclin. Genes Dev 16:3277–3289.
  15. Craven SE, El Husseini AE, Bredt DS (1999): Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron 22:497–509.
  16. Curry CJ, Carey JC, Holland JS, Chopra D, Fineman R, Golabi M, Sherman S, Pagon RA, Allanson J, Shulman S (1987): Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45–57.
  17. Del Rio JA, Gonzalez-Billault C, Urena JM, Jimenez EM, Barallobre MJ, Pascual M, Pujadas L, Simo S, La Torre A, Wandosell F, Avila J, Soriano E (2004): MAP1B is required for netrin 1 signaling in neuronal migration and axonal guidance. Curr Biol 14:840–850.
  18. Dent EW, Barnes AM, Tang F, Kalil K (2004): Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton. J Neurosci 24:3002–3012.
  19. Drescher U, Bonhoeffer F, Muller BK (1997): The Eph family in retinal axon guidance. Curr Opin Neurobiol 7:75–80.
  20. Efferth T (2003): Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. Ageing Res Rev 2:11–24.
  21. Eisen MB, Spellman PT, Brown PO, Botstein D (1998): Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868.
  22. El Husseini A, Craven SE, Brock SC, Bredt DS (2001): Polarized targeting of peripheral membrane proteins in neurons. J Biol Chem 276:44984–44992.
  23. Ernsberger U, Sendtner M, Rohrer H (1989): Proliferation and differentiation of embryonic chick sympathetic neurons: effects of ciliary neurotrophic factor. Neuron 2:1275–1284.
  24. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M (2001): Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem 76:391–400.
  25. Fazeli A, Dickinson SL, Hermiston ML, Tighe RV, Steen RG, Small CG, Stoeckli ET, Keino-Masu K, Masu M, Rayburn H, Simons J, Bronson RT, Gordon JI, Tessier-Lavigne M, Weinberg RA (1997): Phenotype of mice lacking functional deleted in colorectal cancer (Dcc) gene. Nature 386:796–804.
  26. Fitzky BU, Moebius FF, Asaoka H, Waage-Baudet H, Xu L, Xu G, Maeda N, Kluckman K, Hiller S, Yu H, Batta AK, Shefer S, Chen T, Salen G, Sulik K, Simoni RD, Ness GC, Glossmann H, Patel SB, Tint GS (2001): 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest 108:905–915.
  27. Flanagan JG, Vanderhaeghen P (1998): The ephrins and Eph receptors in neural development. Annu Rev Neurosci 21:309–345.
  28. Frolov A, Zielinski SE, Crowley JR, Dudley-Rucker N, Schaffer JE, Ory DS (2003): NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. J Biol Chem 278:25517–25525.
  29. Garda AL, Puelles L, Rubenstein JL, Medina L (2002): Expression patterns of Wnt8b and Wnt7b in the chicken embryonic brain suggest a correlation with forebrain patterning centers and morphogenesis. Neuroscience 113:689–698.
  30. Goedert M, Crowther RA, Garner CC (1991a): Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci 14:193–199.
  31. Goedert M, Spillantini MG, Crowther RA (1991b): Tau proteins and neurofibrillary degeneration. Brain Pathol 1:279–286.
  32. Gopalakrishna P, Chaubey SK, Manogaran PS, Pande G (2000): Modulation of alpha5beta1 integrin functions by the phospholipid and cholesterol contents of cell membranes. J Cell Biochem 77:517–528.
  33. Gorlin RJ, Cohen MM, Levin LS (1990): Syndromes of the Head and Neck. New York, Oxford University Press.
  34. Gruneberg H (1943): The development of some external features in 431 mouse embryos. J Heredity 34:89–92.
  35. Guirland C, Suzuki S, Kojima M, Lu B, Zheng JQ (2004): Lipid rafts mediate chemotropic guidance of nerve growth cones. Neuron 42:51–62.
  36. Hagiwara H, Yorifuji H, Sato-Yoshitake R, Hirokawa N (1994): Competition between motor molecules (kinesin and cytoplasmic dynein) and fibrous microtubule-associated proteins in binding to microtubules. J Biol Chem 269:3581–3589.
  37. Harris R, Sabatelli LM, Seeger MA (1996): Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron 17:217–228.
  38. Hashimoto M, Rockenstein E, Crews L, Masliah E (2003): Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med 4:21–36.
  39. Hayden MR, Clee SM, Brooks-Wilson A, Genest J Jr, Attie A, Kastelein JJ (2000): Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency. Curr Opin Lipidol 11:117–122.
  40. Hisanaga S, Uchiyama M, Hosoi T, Yamada K, Honma N, Ishiguro K, Uchida T, Dahl D, Ohsumi K, Kishimoto T (1995): Porcine brain neurofilament-H tail domain kinase: its identification as cdk5/p26 complex and comparison with cdc2/cyclin B kinase. Cell Motil Cytoskeleton 31:283–297.
  41. Honda M, Tint GS, Honda A, Salen G, Shefer S, Batta AK, Matsuzaki Y, Tanaka N (2000): Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome. J Inherit Metab Dis 23:464–474.
  42. Hosoi T, Uchiyama M, Okumura E, Saito T, Ishiguro K, Uchida T, Okuyama A, Kishimoto T, Hisanaga S (1995): Evidence for cdk5 as a major activity phosphorylating tau protein in porcine brain extract. J Biochem (Tokyo) 117:741–749.
  43. Hughes SM, Lillien LE, Raff MC, Rohrer H, Sendtner M (1988): Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature 335:70–73.
  44. Hunt JM, Bommert K, Charlton MP, Kistner A, Habermann E, Augustine GJ, Betz H (1994): A post-docking role for synaptobrevin in synaptic vesicle fusion. Neuron 12:1269–1279.
  45. Irie Y, Keung WM (2003): Anti-amyloid beta activity of metallothionein-III is different from its neuronal growth inhibitory activity: structure-activity studies. Brain Res 960:228–234.
  46. Irons M, Elias ER, Salen G, Tint GS, Batta AK (1993): Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 341:1414.
  47. Katzov H, Chalmers K, Palmgren J, Andreasen N, Johansson B, Cairns NJ, Gatz M, Wilcock GK, Love S, Pedersen NL, Brookes AJ, Blennow K, Kehoe PG, Prince JA (2004): Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism. Hum Mutat 23:358–367.
  48. Kaufman MH (1992): The Atlas of Mouse Development. London, Academic 449.
  49. Kearsey JM, Coates PJ, Prescott AR, Warbrick E, Hall PA (1995): Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 11:1675–1683.
  50. Kelley RI, Hennekam RC (2000): The Smith-Lemli-Opitz syndrome. J Med Genet 37:321–335.
  51. Kelley RI, Herman GE (2001): Inborn errors of sterol biosynthesis. Annu Rev Genomics Hum Genet 2:299–341.
  52. Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC, Palumbos JC, Muenke M (1996): Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? Am J Med Genet 66:478–484.
  53. Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H (1999): Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J Neurosci 19:8244–8251.
  54. Kohler LB, Berezin V, Bock E, Penkowa M (2003): The role of metallothionein II in neuronal differentiation and survival. Brain Res 992:128–136.
  55. Kutzleb C, Sanders G, Yamamoto R, Wang X, Lichte B, Petrasch-Parwez E, Kilimann MW (1998): Paralemmin, a prenyl-palmitoyl-anchored phosphoprotein abundant in neurons and implicated in plasma membrane dynamics and cell process formation. J Cell Biol 143:795–813.
  56. Landino LM, Iwig JS, Kennett KL, Moynihan KL (2004): Repair of peroxynitrite damage to tubulin by the thioredoxin reductase system. Free Radic Biol Med 36:497–506.
  57. Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G, Kaminski WE, Schmitz G (1999): Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun 257:29–33.
  58. Lauderdale JD, Pasquali SK, Fazel R, van Eeden FJ, Schauerte HE, Haffter P, Kuwada JY (1998): Regulation of netrin-1a expression by hedgehog proteins. Mol Cell Neurosci 11:194–205.
  59. Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL (1996): Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680.
  60. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001): CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357.
  61. Mitchell KJ, Doyle JL, Serafini T, Kennedy TE, Tessier-Lavigne M, Goodman CS, Dickson BJ (1996): Genetic analysis of Netrin genes in Drosophila: Netrins guide CNS commissural axons and peripheral motor axons. Neuron 17:203–215.
  62. Mitter D, Reisinger C, Hinz B, Hollmann S, Yelamanchili SV, Treiber-Held S, Ohm TG, Herrmann A, Ahnert-Hilger G (2003): The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content. J Neurochem 84:35–42.
  63. Nakamura Y, Sakakibara J, Izumi T, Shibata A, Ono T (1996): Transcriptional regulation of squalene epoxidase by sterols and inhibitors in HeLa cells. J Biol Chem 271:8053–8056.
  64. Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P (2000): Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290:2298–2301.
  65. Ness GC, Lopez D, Borrego O, Gilbert-Barness E (1997): Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels. Am J Med Genet 68:294–299.
  66. Novak A, Dedhar S (1999): Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci 56:523–537.
  67. Nowaczyk MJ, Nakamura LM, Eng B, Porter FD, Waye JS (2001): Frequency and ethnic distribution of the common DHCR7 mutation in Smith-Lemli-Opitz syndrome. Am J Med Genet 102:383–386.
  68. Nusse R, Varmus HE (1992): Wnt genes. Cell 69:1073–1087.
  69. Opitz JM, de la Cruz F (1994): Cholesterol metabolism in the RSH/Smith-Lemli-Opitz syndrome: summary of an NICHD conference. Am J Med Genet 50:326–338.
  70. Opitz JM, Gilbert-Barness E, Ackerman J, Lowichik A (2002): Cholesterol and development: the RSH (‘Smith-Lemli-Opitz’) syndrome and related conditions. Pediatr Pathol Mol Med 21:153–181.
  71. Oppenheim RW, Prevette D, Yin QW, Collins F, MacDonald J (1991): Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science 251:1616–1618.
  72. Oram JF, Wolfbauer G, Vaughan AM, Tang C, Albers JJ (2003): Phospholipid transfer protein interacts with and stabilizes ATP-binding cassette transporter A1 and enhances cholesterol efflux from cells. J Biol Chem 278:52379–52385.
  73. Park JY, Lansbury PT Jr (2003): Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson’s disease. Biochemistry 42:3696–3700.
  74. Parr BA, McMahon AP (1994): Wnt genes and vertebrate development. Curr Opin Genet Dev 4:523–528.
  75. Penkowa M, Carrasco J, Giralt M, Moos T, Hidalgo J (1999): CNS wound healing is severely depressed in metallothionein I- and II-deficient mice. J Neurosci 19:2535–2545.
  76. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, Taylor FR, Wang EA, Galdes A (1998): Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273:14037–14045.
  77. Pola R, Flex A, Gaetani E, Santoliquido A, Serricchio M, Pola P, Bernabei R (2003): Intercellular adhesion molecule-1 K469E gene polymorphism and Alzheimer’s disease. Neurobiol Aging 24:385–387.
  78. Porter FD (2000): RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Mol Genet Metab 71:163–174.
  79. Renaudin A, Lehmann M, Girault J, McKerracher L (1999): Organization of point contacts in neuronal growth cones. J Neurosci Res 55:458–471.
  80. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R (2004): SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet 36:247–255.
  81. Rousseau F, Vincent A, Rivella S, Heitz D, Triboli C, Maestrini E, Warren ST, Suthers GK, Goodfellow P, Mandel JL (1991): Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA). Am J Hum Genet 48:108–116.
  82. Rowe AH, Argmann CA, Edwards JY, Sawyez CG, Morand OH, Hegele RA, Huff MW (2003): Enhanced synthesis of the oxysterol 24(S),25-epoxycholesterol in macrophages by inhibitors of 2,3-oxidosqualene:lanosterol cyclase: a novel mechanism for the attenuation of foam cell formation. Circ Res 93:717–725.
  83. Rudge JS, Eaton MJ, Mather P, Lindsay RM, Whittemore SR (1996): CNTF induces raphe neuronal precursors to switch from a serotonergic to a cholinergic phenotype in vitro. Mol Cell Neurosci 7:204–221.
  84. Ryan AK, Bartlett K, Clayton P, Eaton S, Mills L, Donnai D, Winter RM, Burn J (1998): Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet 35:558–565.
  85. Santiard-Baron D, Gosset P, Nicole A, Sinet PM, Christen Y, Ceballos-Picot I (1999): Identification of beta-amyloid-responsive genes by RNA differential display: early induction of a DNA damage-inducible gene, gadd45. Exp Neurol 158:206–213.
  86. Schmitz G, Langmann T (2001): Structure, function and regulation of the ABC1 gene product. Curr Opin Lipidol 12:129–140.
  87. Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, Tessier-Lavigne M (1996): Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87:1001–1014.
  88. Shetty KT, Link WT, Pant HC (1993): cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc Natl Acad Sci USA 90:6844–6848.
  89. Shu T, Butz KG, Plachez C, Gronostajski RM, Richards LJ (2003): Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J Neurosci 23:203–212.
  90. Shu T, Valentino KM, Seaman C, Cooper HM, Richards LJ (2000): Expression of the netrin-1 receptor, deleted in colorectal cancer (DCC), is largely confined to projecting neurons in the developing forebrain. J Comp Neurol 416:201–212.
  91. Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O’Connor PM, Fornace AJ Jr (1994): Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266:1376–1380.
  92. Smith DW, Lemli L, Opitz JM: A newly recognized syndrome of multiple congenital abnormalities. J Pediatr 64:210–217.
  93. Strahle U, Fischer N, Blader P (1997): Expression and regulation of a netrin homologue in the zebrafish embryo. Mech Dev 62:147–160.
  94. Tepass U, Truong K, Godt D, Ikura M, Peifer M (2000): Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol 1:91–100.
  95. Tessier-Lavigne M, Goodman CS (1996): The molecular biology of axon guidance. Science 274:1123–1133.
  96. Theil T, Aydin S, Koch S, Grotewold L, Ruther U (2002): Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development 129:3045–3054.
  97. Thibault C, Lai C, Wilke N, Duong B, Olive MF, Rahman S, Dong H, Hodge CW, Lockhart DJ, Miles MF (2000): Expression profiling of neural cells reveals specific patterns of ethanol-responsive gene expression. Mol Pharmacol 58:1593–1600.
  98. Tierney E, Nwokoro NA, Kelley RI (2000): Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome. Ment Retard Dev Disabil Res Rev 6:131–134.
  99. Tierney E, Nwokoro NA, Porter FD, Freund LS, Ghuman JK, Kelley RI (2001): Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet 98:191–200.
  100. Tint GS (1999): A mouse model for the Smith Lemli Opitz syndrome (SLOS) (abstract). Am J Hum Genet 65(suppl 4):96.
  101. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G (1994): Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107–113.
  102. Torp R, Su JH, Deng G, Cotman CW (1998): GADD45 is induced in Alzheimer’s disease, and protects against apoptosis in vitro. Neurobiol Dis 5:245–252.
  103. Trendelenburg G, Prass K, Priller J, Kapinya K, Polley A, Muselmann C, Ruscher K, Kannbley U, Schmitt AO, Castell S, Wiegand F, Meisel A, Rosenthal A, Dirnagl U (2002): Serial analysis of gene expression identifies metallothionein-II as major neuroprotective gene in mouse focal cerebral ischemia. J Neurosci 22:5879–5888.
  104. Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991): The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein. Neuron 7:337–347.
  105. Verbeek MM, Otte-Holler I, Wesseling P, Ruiter DJ, de Waal RM (1996): Differential expression of intercellular adhesion molecule-1 (ICAM-1) in the A beta-containing lesions in brains of patients with dementia of the Alzheimer type. Acta Neuropathol (Berl) 91:608–615.
  106. Vuletic S, Jin LW, Marcovina SM, Peskind ER, Moller T, Albers JJ (2003): Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer’s disease. J Lipid Res 44:1113–1123.
  107. Waage-Baudet H, Lauder JM, Dehart DB, Kluckman K, Hiller S, Tint GS, Sulik KK (2003): Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism. Int J Dev Neurosci 21:451–459.
  108. Wallingford JB, Vogeli KM, Harland RM (2001): Regulation of convergent extension in Xenopus by Wnt5a and Frizzled-8 is independent of the canonical Wnt pathway. Int J Dev Biol 45:225–227.
  109. Wassif CA, Zhu P, Kratz L, Krakowiak PA, Battaile KP, Weight FF, Grinberg A, Steiner RD, Nwokoro NA, Kelley RI, Stewart RR, Porter FD (2001): Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. Hum Mol Genet 10:555–564.
  110. Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, Duran M, Jira PE, Smeitink JA, Wevers RA, Wanders RJ (1998): Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet 63:329–338.
  111. Waye JS, Nakamura LM, Eng B, Hunnisett L, Chitayat D, Costa T, Nowaczyk MJ (2002): Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. J Med Genet 39:E31.

    External Resources

  112. Wianny F, Real FX, Mummery CL, Van Rooijen M, Lahti J, Samarut J, Savatier P (1998): G1-phase regulators, cyclin D1, cyclin D2, and cyclin D3: up-regulation at gastrulation and dynamic expression during neurulation. Dev Dyn 212:49–62.
  113. Wodicka L, Dong H, Mittmann M, Ho MH, Lockhart DJ (1997): Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol 15:1359–1367.
  114. Wollmer MA, Streffer JR, Lutjohann D, Tsolaki M, Iakovidou V, Hegi T, Pasch T, Jung HH, Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003): ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease. Neurobiol Aging 24:421–426.
  115. Zhang L, Wang L, Ravindranathan A, Miles MF (2002): A new algorithm for analysis of oligonucleotide arrays: application to expression profiling in mouse brain regions. J Mol Biol 317:225–235.
  116. Zhao C, Pleasure SJ (2004): Frizzled-9 promoter drives expression of transgenes in the medial wall of the cortex and its chief derivative the hippocampus. Genesis 40:32–39.

Pay-per-View Options
Direct payment This item at the regular price: USD 9.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 8.00