Gene expression in fetal Down Syndrome brain as revealed by subtractive hybridization
Information on gene expression in brain of patients with Down Syndrome (DS, trisomy 21) is limited and molecular biological research is focussing on mapping and sequencing chromosome 21. The information on gene expression in DS available follows the current concept of a gene dosage effect due to a third copy of chromosome 21 claiming overexpression of genes encoded on this chromosome.
Based upon the availability of fetal brain and recent technology of gene hunting, we decided to use subtractive hybridization to evaluate differences in gene expression between DS and control brains.
Subtractive hybridization was applied on two fetal brains with DS and two age and sex matched controls, 23rd week of gestation, and mRNA steady state levels were evaluated generating a subtractive library. Subtracted sequences were identified by gene bank and assigned by alignments to individual genes.
We found a series of up-and downregulated sequences consisting of chromosomal transcripts, enzymes of intermediary metabolism, hormones, transporters/channels and transcription factors (TFs).
We show that trisomy 21 or aneuploidy leads to the deterioration of gene expression and the derangement of transcripts described describes the involvement of chromosomes other than chromosome 21, explains impairment of transport, carriers, channels, signaling, known metabolic and hormones imbalances. The dys-coordinated expression of transcription factors including homeobox genes, POU-domain TFs, helix-loop-helix-motifs, LIM domain containing TFs, leucine zippers, forkhead genes, maybe of pathophysiological significance for abnormal brain development and wiring found in patients with DS. This is the first description of the concomitant expression of a large series of sequences indicating disruption of the concerted action of genes in that disorder.
KeywordsDown Syndrome Chromosomal Transcript mRNA Steady State Level Subtractive Library Thyroid Stimulate Hormone Receptor
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.
Bauer D, Warthoe P, Rohde L, Struss M (1994) In: PCR methods and applications. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp S97–S108Google Scholar
Bertioli DJ, Schlichter UHA, Adams MJ, Burrow PR, Steinbiss HH, Antoniew JF (1995) An analysis of differential display shows a strong bias towards high copy number messenger RNAs. Nucl Acids Res 23: 4520–4523PubMedCrossRefGoogle Scholar
Brodsky G, Barnes T, Bleskan J, Becker L, Cox M, Patterson D (1997) The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down Syndrome. Hum Mol Genet 6: 2043–2050PubMedCrossRefGoogle Scholar
Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in Down Syndrome. Nature 378: 776–779PubMedCrossRefGoogle Scholar
Castells S, Beaulieu I, Torrado C, Wisniewski KE, Zarny S, Gelato MC (1996) Hypothalamic versus pituitary dysfunction in Down’s Syndrome as cause of growth retardation. J Intellect Disabil Res 40: 509–517PubMedGoogle Scholar
Chen H, Morris MA, Rossier C, Blouin JL, Antonorakis SE (1995) Cloning of the cDNA for the human ATP synthase OSCP subunit (ATP50) by exon trapping and mapping to chromosome 21q22.1-q22.2. Genomics 28: 470–476PubMedCrossRefGoogle Scholar
Crawford MJ, Lanctot C, Tremblay JJ, Jenkins N, Gilbert D, Copeland N, Beatty B, Drouin J (1997) Humana and murine PTX1/Ptx1 gene maps to the region for Treacher-Collins syndrome. Mamm Genome 8: 841–850PubMedCrossRefGoogle Scholar
De la Monte SM, Xu YY, Hutchins GM, Wands JR (1996) Developmental patterns of neuronal thread protein gene expression in Down Syndrome. J Neurol Sci 135:118–125PubMedCrossRefGoogle Scholar
Epstein CJ (1992) 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
Finn JT, Grunwald ME, Yau KW (1996) Cyclic nucleotide-gated ion chann els: an extended family with diverse functions. Ann Rev Physiol 58: 395–426CrossRefGoogle Scholar
Goodison KL, Parhad IM, White CL, Sima AA, Clark AW (1993) Neuronal and glial gene expression in neocortex of Down’s syndrome and Alzheimer’s disease. J Neuropathol Exp Neurol 52: 192–198PubMedCrossRefGoogle Scholar
Gosset P, Ghezala GA, Korn B, Yaspo ML, Poutska A, Lehrach H, Sinet PM, Creau N (1997) A new inward rectifier potassium channel gene localized on chromosome 21 in the Down Syndrome chromosomal region 1 (DCR1). Genomics 44: 237–241PubMedCrossRefGoogle Scholar
Kageyama R, Sasai Y, Akazewa C, Ishibashi M, Takebayashi K, Shimizu C, Tornita K, Nakanishi S (1995) Regulation of mammalian neural development by helix — loop — helix transcription factors. Crit Rev Neurobiol 9: 177–188PubMedGoogle Scholar
Kakigi R, Kuroda Y (1992) Brain-stem auditory evoked potentials in adults with Down Syndrome. Electroencephalogr Clin Neurophysiol 84: 293–295PubMedCrossRefGoogle Scholar
Kaltschmidt B, Baeuerle PA, Kaltschmidt C (1993) Potential involvement of the transcription factor NF-kappa-B in neurological disorders. Mol Aspects Med 14:171–190PubMedCrossRefGoogle Scholar
Kaufmann E, Knöchel W (1996) Five years on the wings of forkhead. Mech Dev 57: 3–20PubMedCrossRefGoogle Scholar
Labudova O, Lubec G (1998) cAMP upregulates the transposable element mys-1: a possible link between signaling and mobile DNA. Life Sci 62: 431–437PubMedCrossRefGoogle Scholar
Labudova O, Cairns N, Yeghiazaryan K, Lubec G (1998) The upregulation of vasopressin in brain of patients with Down Syndrome and Alzheimer’s disease. Brain Res 806: 55–59PubMedCrossRefGoogle Scholar
Labudova O, Kitzmüller E, Köck Th, Cairns N, Lubec G (1998) Overexpression of the thyroid stimulating hormone receptor in brain of patients with Down Syndrome. Life Sci 64: 1037–1044CrossRefGoogle Scholar
Labudova O, Krapfenbauer K, Cairns N, Lubec G (1998) Decreased junD in brain of patients with Down Syndrome. Neurosci Lett 252: 159–162PubMedCrossRefGoogle Scholar
Lanctot C, Lamolet B, Drouin J (1997) The bicoid-related homeoprotein Ptx1 defines the most anterior domain for the embryo and differentiates posterior from anterior lateral mesoderm. Development 124: 2807–2817PubMedGoogle Scholar
Malo MS, Srivastava K, Ingram VM (1995) Gene assignment by polymerase chain reaction: localization of the human potassium channel IsK gene to the Down’s syndrome region of chromosome 21q11.1-q22.2. Gene 159: 273–275PubMedCrossRefGoogle Scholar
Marks A, O’Hanlon D, Lei M, Percy ME, Becker LE (1996) Accujmulation of S100 beta mRNA and protein in cerebellum during infancy in Down Syndrome and control subjects. Brain Res-Mol Brain Res 36: 343–348PubMedCrossRefGoogle Scholar
Naylor GJ, Semple M, Irvine EA (1993) Erythrocyte membrane cation carrier in Down Syndrome. Clin Genet 43: 9–10PubMedCrossRefGoogle Scholar
Ohira M, Seki N, Nagase T, Suzuki E, Nomura N, Ohara O, Hattori M, Sakaki Y, Eki T, Murakami Y, Saito T, Ichikawa H, Ohki M (1997) Gene ideentification in 1.6-Mb region of the Down syndrome region on chromosome 21. Genome Res 7: 47–58PubMedCrossRefGoogle Scholar
Oyama F, Cairns NJ, Shimada H, Oyama R, Titani K, Ihara Y (1994) Down’s syndrome: upregulation of beta-amyloid protein precursor and tau mRNAs and their defective cooredination. J Neurochem 62: 1062–1066PubMedCrossRefGoogle Scholar
Pash J, Smithgall T, Bustin M (1991) Chromosomal protein HMG-14 is overexpressed in Down Syndrome. Exp Cell Res 193: 232–235PubMedCrossRefGoogle Scholar
Pietrini P, Dani A, Furey ML, Alexander GE, Freo U, Grady CL, Mentis MJ, Mangot D, Simon EW, Horwitz B, Haxby JV, Schapiro MB (1997) Low glucose metabolism during brain stimulation in older Down’s syndrome subjects at risk for Alzheimer’s disease prior to dementia. Am J Psychiatry 154: 1063–1069PubMedGoogle Scholar
Pueschel SM (1993) Growth hormone response after administration of L-dopa, Clonidine, and growth hormone releasing hormone in children with Down Syndrome. Res Dev Disabil 14: 291–298PubMedCrossRefGoogle Scholar
Sanchez-Garcia I, Rabbitts TH (1994) The Lim-domain: a new structural motif found in zinc-finger like proteins. Trends Genet 10: 315–320PubMedCrossRefGoogle Scholar
Schapiro MB, Grady CL, Haxby JV (1992) Nature of mental retardation and dementia in Down’s syndrome: study with PET, CT and neuropsychology. Neurobiol Aging 13: 723–734PubMedCrossRefGoogle Scholar
Sharp ZD, Morgan WW (1996) Brain POU-er. Bioassays 18: 347–350CrossRefGoogle Scholar
Sompayrac L, Jane S, Burn TC, Tenen DG, Danna KJ (1995) Overcoming limitations of the messenger RNA differential display technique. Nucl Acids Res 23: 4738–4739PubMedCrossRefGoogle Scholar
Sordino P, Douboule D, Kondo T (1996) Zebrafish Hoxa and Evx-genes: cloning, developmental expression and implications for the functional evolution of posterior Hox genes. Mech Dev 59: 165–175PubMedCrossRefGoogle Scholar
Stein S, Fritsch R, Lemaire L, Kessel M (1996) Checklist: vertebrate homeobox genes. Mech Dev 55: 91–108PubMedCrossRefGoogle Scholar
Stewart GJ, Davies RW (1997) In: Davies RW, Morris BJ (eds) Molecular biology of the neuron. Bios Scientifique publishers, Oxford UK, pp 1–18Google Scholar
Struhl K (1989) Helix-turn-helix, zinc finger, and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins. Trends Biochem Sci 14: 137–140PubMedCrossRefGoogle Scholar
© Springer-Verlag Wien 1999