Aberrant expression of dihydropyrimidinase related proteins-2,-3 and -4 in fetal Down Syndrome brain
Pathfinding of growing axons to reach their target during brain development is a subtle process needed to build up contacts between neurons. Abnormalities in brain development in Down Syndrome (DS) are described in a couple of morphological reports but the molecular mechanisms underlying abnormal wiring in fetal DS brain are not yet elucidated. We therefore performed a study using the proteomic approach to show differences in protein levels involved in the guidance of axons between control and DS brain in early prenatal life. Proteins obtained from autopsy of human fetal abortus were applied on 2-dimensional gel, identified and quantified. We quantified 5 members of the semaphorin/collapsin family, the dihydropyrimidinase related proteins 1—4 and the collapsin response mediator protein-5 (CRMP-5) in 8 DS and 7 control cortex samples. DRP-1 and CRMP-5 levels were comparable in the control and DS samples.
DRP-1 and CRMP-5 levels were comparable in the control and DS samples.
Evaluation of DRP-2, DRP-3 and DRP-4 revealed significantly decreased levels of 2 of the 15 spots assigned to DRP-2 and increased levels of one spot assigned to DRP-3 and increased DRP-4 in DS brain.
We conclude that as early as from the 19th week of gestation pathfinding cues of the outgrowing axons are impaired in DS. These findings may help to elucidate mechanisms leading to abnormalities in neural migration of DS brain.
KeywordsDown Syndrome Growth Cone Collapsin Response Mediator Protein Down Syndrome Patient Collapsin Response Mediator
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Arimura N, Inagaki N, Chirara K, Menager C, Nakamura N, Amanot M, Iwamatsu A,Goshima Y, Kaibuchi K (2000) Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. J Biol Chem 275: 23973–23980PubMedCrossRefGoogle Scholar
Becker L, Mito T, Takashima S, Onodera K (1991) Growth and development of the brain in Down syndrome. In: Epstein CJ (ed) The morphogenesis of Down syndrome.Wiley-Liss, New York, p 133Google Scholar
Berndt P, Hobolm U, Langen H (1999) Reliable automatic protein identification from matrix-assisted laser desorption/ionisation mass spectrometric peptide fingerprints.Electrophoresis 20: 3521–3526PubMedCrossRefGoogle Scholar
Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
Byk T, Dobransky T, Cifuentes-Diaz C, Sobel A (1996) Identification and molecular characterization of unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product. J Neurosci 16: 688–701PubMedGoogle Scholar
Engidawork E, Balic N, Fountoulakis M, Dierssen M, Lubec G (2001) ß-Amyloid precursor protein, ETS-2 and collagen alpha 1 (VI) precursor, encoded on chromosome 21,are not overexpressed in fetal Down Syndrome: further evidence against gene dosage effect. J Neural Transm (this volume)Google Scholar
Epstein CJ (1995) Down syndrome (Trisomy 21). In: Scriver CR, Beaudet AL, Sly WS,Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw Hill,New York, pp 749–794Google Scholar
Fountoulakis M, Langen H (1997) Identification of proteins by matrix-assisted laser desorption ionisation-mass spectrometry following in-gel digestion in low-salt, nonvolatile buffer and simplified peptide recovery. Anal Biochem 250: 153–156PubMedCrossRefGoogle Scholar
Fukada M, Watakabe I, Yuasa-Kawada J, Kawachi H, Kuriowa A, Matsuda Y, Noda M (2000) Molecular characterization of CRMP5, a novel member of the collapsin response mediator protein family. J Biol Chem 275: 37957–37965PubMedCrossRefGoogle Scholar
Goshima Y, Nakamura F, Strittmatter P, Strittmatter S (1995) Collapsin-induced growth cone collapse by an intracellular protein related to unc-33. Nature 376: 509–514PubMedCrossRefGoogle Scholar
Greber-Platzer S, Shatzmann-Turhani D, Wollenek G, Lubec G (1999) Evidence against the current hypothesis of “gene dosage effect” of trisomy 21: ets-2, encoded on chromosome 21’ is not overexpressed in hearts of patients with Down Syndrome. Biochem Biophys Res Commun 254: 395–399PubMedCrossRefGoogle Scholar
Gu Y, Ihara Y (2000) Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J Biol Chem 275: 17917–17920PubMedCrossRefGoogle Scholar
Hamajima N, Matsuda K, Sakata S, Tamaki N, Sasaki M, Nonaka M (1996) A novel gene family defined by human dihydropyrimididnase and the three related proteins with differential tissue distribution. Gene 180: 157–163PubMedCrossRefGoogle Scholar
He X, Rosenfeld MG (1991) Mechanisms of complex transcriptional regulation: implications for brain development. Neuron 17: 183–196CrossRefGoogle Scholar
Kato Y, Hamajima N, Inagaki H, Okamura T, Kojin T, Sasaki M, Nonaka M (1998) Postmeiotic expression of the mouse dihydrpyrimidinase-related protein 3 (DRP3) gene during spermiogenesis. Mol Reprod Dev 51: 105–111PubMedCrossRefGoogle Scholar
Knupp C, Squire JM (2001) A new twist in the collagen story-the type VI segmented super coil. EMBO J 20: 372–376PubMedCrossRefGoogle Scholar
Koyama K, Sudo K, Nakamura Y (1995) Isolation of 115 human chromosome 8-specific expressed-sequence tags by exon amplification. Genomics 26: 245–253PubMedCrossRefGoogle Scholar
Langen H, Roder D, Juranville J, Fountoulakis M (1997) Effect of protein application mode and acrylamide concentration on the resolution of protein spots separated by two-dimensional gel electrophoresis. Electrophoresis 18: 2085–2090PubMedCrossRefGoogle Scholar
Lubec G, Nonaka M, Krapfenbauer K, Gratzer M, Cairns N, Fountoulakis M (1999) Expression of the dihydropyrimidinase related protein 2 (DRP-2) in Down syndrome and Alzheimer’s disease brain is downregulated at the mRNA and dysregulated at the protein level. J Neural Transm [Suppl] 57: 161–177Google Scholar
Luo Y, Raible D, Raper J (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cone. Cell 75: 217–227PubMedCrossRefGoogle Scholar
Marin-Padilla M (1976) Pyamidal cell abnormalities in the motor cortex of a child with Down syndrome. J Comp Neurol 167: 63–75PubMedCrossRefGoogle Scholar
Matsuo T, Staffer JK, Walker RL, Meltzer P, Thiele CJ (2000) Structure and promotor analysis of the human unc-33-like phosphoprotein gene: E-box required for maximal expression in neuroblastoma and myeloblasts. J Biol Chem 275: 16560–16568PubMedCrossRefGoogle Scholar
Minturn JE, Fryer HJ, Geschwind DH, Hockfield S (1995) TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth. J Neurosci 15: 6757–6766PubMedGoogle Scholar
Nakamura F, Kalb RG, Strittmatter SM (2000) Molecular basis of semaphorin-mediated axon guidance. J Neurobiol 44: 219–229PubMedCrossRefGoogle Scholar
Pasterkamp RJ, De Winter F, Holtmaat AJ, Verhagen J (1998) Evidence for a role of the chemorepellent semaphoring III and ist receptor neuropilin-1 in the regeneration of primary olfactory axons. J Neurosci 18: 9962–9976PubMedGoogle Scholar
Quinn C, Gray G, Hockfield S (1999) A family of proteins implicated in axon guidance and outgrowth. J Neurobiol 41: 158–164PubMedCrossRefGoogle Scholar
Sanes JR, Jessell TM (2000) The guidance of axons to their targets. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neural science. McGraw Hill, New York, pp 1063–1086Google Scholar
Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274: 1123–1133PubMedCrossRefGoogle Scholar
Trüeb B, Bornstein P (1984) Characterization of the precursor form of type VI collagen. J Biol Chem 259: 8597–8604PubMedGoogle Scholar
Wang LH, Strittmatter SM (1997) Brain CRMP forms heterotetramers similar to liver dihydropyrimidinase. J Neurochem 69: 2261–2269PubMedCrossRefGoogle Scholar
Wisniewski KE, Bobinski M (1991) Hypothalamic abnormalities in Down syndrome. In: Epstein CJ (ed) The morphogenesis of Down syndrome. Wiley-Liss, New York, p 133Google Scholar
Wisniewski KE, Kida E (1994) Abnormal neurogenesis and synaptogenesis in Down syndrome brain. Dev Brain Dysfunct 7: 289–301Google Scholar
Yoshida H, Watanabe A, Ihara Y (1998) Collapsin response mediator protein-2 is associated with neurofibillary tangles in Alzheimer’s disease. J Biol Chem 273: 9761–9768PubMedCrossRefGoogle Scholar
© Springer-Verlag/Wien 2001