Zusammenfassung
Störungen in der pränatalen Gehirnentwicklung und/oder postnatalen -reifung im Zusammenhang
mit der Ätiologie und Pathophysiologie schizophrener Psychosen sind unter dem Begriff
der Entwicklungshypothese der Schizophrenien bekannt. Diese wird durch Befunde der
Bildgebung und neuroanatomische Untersuchungen bei schizophrenen Patienten unterstützt.
Zelladhäsionsmoleküle, wie z. B. die Cadherine, sind von zentraler Bedeutung für morphogenetische
Prozesse im ZNS während der Embryonalentwicklung. Aktuelle Untersuchungen zur Genorganisation
und der chromosomalen Lokalisation der Cadherine zeigen einen Zusammenhang mit Kopplungsbefunden
in Familien mit schizophrenen Erkrankungen. Diese Befunde lassen es angebracht erscheinen,
die Rolle der Cadherine bei der Pathogenese schizophrener Erkrankungen zu untersuchen.
Abstract
Disturbance of prenatal brain development and/or postnatal brain maturation in the
context of the etiology and pathophysiology of schizophrenic psychoses is increasingly
recognized as the developmental hypothesis of schizophrenia. This hypothesis is based
on findings in neuroimaging and neuroanatomical findings in schizophrenic disorders.
Cell adhesion molecules, such as the cadherins, are of critical importance for morphogenesis
in the CNS during embryonic development. Recent investigations of the genomic organization
and chromosomal localization of cadherins show a remarkable association with linkage
results in affected multiplex pedigrees. Taken together, these findings should lead
to an investigation of the role of cadherins in complex psychiatric disorders.
Literatur
- 1 Bunney W E. Neurodevelopmental hypothesis of schizophrenia. In: Charney DS; Nestler
EJ; Bunney BS, eds. Neurobiology of Mental Illness. Oxford: Oxford University Press
1999: 225-235
- 2 Bogerts B. The neuropathology of schizophrenia: Pathophysiological and neurodevelopmental
implications. In: Mednick SA; Cannon TD; Barr CE, eds. Fetal neural development and
adult schizophrenia. Cambridge: Cambridge University Press 1991: 153-173
- 3 Bogerts B. Hirnstrukturelle Untersuchungen an schizophrenen Patienten. In: Lieb
K; Riemann D; Berger M, eds. Biologisch-psychiatrische Forschung - Ein Überblick.
Stuttgart: Fischer-Verlag 1995: 123-144
- 4
Lieberman J, Bogerts B, Degreef G, Ashtari M, Lantos G, Alvir J.
Qualitative assessment of brain morphology in acute and chronic schizophrenia.
Am J Psychiatry.
1992;
149
784-791
- 5
Arnold S E, Trojanowski J Q.
Recent advances in defining the neuropathology of schizophrenia.
Acta Neuropathol (Berl).
1996;
92
217-231
- 6
Senitz D, Winkelmann E.
Morphology of the orbitofrontal cortex in persons with schizophrenic psychoses. A
Golgi and electron microscopy study.
Psychiatr Neurol Med Psychol (Leipz).
1981;
33
1-9
- 7
Andreasen N C, Olsen S A, Dennert J W, Smith M R.
Ventricular enlargement in schizophrenia: relationship to positive and negative symptoms.
Am J Psychiatry.
1982;
139
297-302
- 8 Huber G. Chronische Schizophrenie. Synopsis klinischer und neuroradiologischer Untersuchungen
an defektschizophrenen Anstaltspatienten. Einzeldarstellungen aus der theoretischen
und klinischen Medizin. Heidelberg: Hüthig 1961
- 9
Johnstone E C, Crow T J, Frith C D, Husband J, Kreel L.
Cerebral ventricular size and cognitive impairment in chronic schizophrenia.
Lancet.
1976;
2
924-926
- 10
Walker E F, Lewine R R, Neumann C.
Childhood behavioral characteristics and adult brain morphology in schizophrenia.
Schizophr Res.
1996;
22
93-101
- 11
Weinberger D R, Bigelow L B, Kleinman J E, Klein S T, Rosenblatt J E, Wyatt R J.
Cerebral ventricular enlargement in chronic schizophrenia. An association with poor
response to treatment.
Arch Gen Psychiatry.
1980;
37
11-13
- 12
Raz S.
Structural cerebral pathology in schizophrenia: regional or diffuse?.
J Abnorm Psychol.
1993;
102
445-452
- 13
Beckmann H, Lauer M.
The human striatum in schizophrenia. II. Increased number of striatal neurons in schizophrenics.
Psychiatry Res.
1997;
68
99-109
- 14
Chakos M H, Lieberman J A, Bilder R M, Borenstein M, Lerner G, Bogerts B, Wu H, Kinon B,
Ashtari M.
Increase in caudate nuclei volumes of first-episode schizophrenic patients taking
antipsychotic drugs.
Am J Psychiatry.
1994;
151
1430-1436
- 15
Falkai P, Schneider T, Greve B, Klieser E, Bogerts B.
Reduced frontal and occipital lobe asymmetry on the CT-scans of schizophrenic patients.
Its specificity and clinical significance.
J Neural Transm Gen Sect.
1995;
99
63-77
- 16
Beckmann H, Jakob H.
Pränatale Entwicklungsstörungen von Hirnstrukturen bei schizophrenen Psychosen.
Nervenarzt.
1994;
65
454-463
- 17
Goldman-Rakic P.
Cerebral cortical mechanisms in schizophrenia.
Neuropsychopharmacol.
1994;
10
22-27
- 18
Jakob H, Beckmann H.
Prenatal developmental disturbances in the limbic allocortex in schizophrenics.
J Neural Transm.
1986;
65
303-326
- 19
Jakob H, Beckmann H.
Circumscribed malformation and nerve cell alterations in the entorhinal cortex of
schizophrenics. Pathogenetic and clinical aspects.
J Neural Transm Gen Sect.
1994;
98
83-106
- 20
Papez J W.
A proposed mechanism of emotion.
Arch Neurol Psychiat.
1937;
38
725-743
- 21
Weinberger D R.
Implications of normal brain development for the pathogenesis of schizophrenia.
Arch Gen Psychiatry.
1987;
44
660-669
- 22
Lieberman J A.
Pathophysiologic mechanisms in the pathogenesis and clinical course of Schizophrenia.
J Clin Psychiatry.
1999;
60 (suppl 12)
9-12
- 23 Colman D R. Cell Adhesion Molecules. In: Siegel GJ; Agranoff BW; Albers RW et al.,
eds, translator and editor Basic Neurochemistry. Philadelphia: Lippincott Williams
& Wilkins 1999: 139-153
- 24
Cunningham B A.
Cell adhesion molecules as morphoregulators.
Curr Opin Cell Biol.
1995;
7
628-633
- 25 Müller W A, Hassel M. Entwicklungsbiologie der Tiere und des Menschen. In: translator
and editor. Berlin Heidelberg New York: Springer-Verlag 1999: 349-352
- 26
Takeichi M.
The cadherins: cell-cell adhesion molecules controlling animal morphogenesis.
Development.
1988;
102
639-655
- 27
Steinberg M S, McNutt P M.
Cadherins and their connections: adhesion junctions have broader functions.
Curr Opin Cell Biol.
1999;
11
554-560
- 28
Tepass U.
Genetic analysis of cadherin function in animal morphogenesis.
Curr Opin Cell Biol.
1999;
11
540-548
- 29
Vogel G.
Tracking the movements that shape an embryo.
Science.
2000;
288
86-87
- 30
Steinberg M S.
Does differential adhesion govern self-assembly processes in histogenesis? Equilibrium
configurations and the emergence of a hierarchy among populations of embryonic cells.
J Exp Zool.
1970;
173
395-434
- 31 Wolpert L. Principles of development. In: translator and editor. Oxford: Oxford
University Press 1998: 232-235
- 32
Gumbiner B M, Yamada K M.
Cell-to-cell contact and extracellular matrix.
Curr Opin Cell Biol.
1995;
7
615-618
- 33
Redies C.
Cadherins in the central nervous system.
Prog Neurobiol.
2000;
61
611-648
- 34
Fawcett J W, Keynes R J.
Peripheral nerve regeneration.
Annu Rev Neurosci.
1990;
13
43-60
- 35
Nollet F, Kools P, Roy F.
Phylogenetic analysis of the cadherin superfamily allows identification of six major
subfamilies besides several solitary members.
J Mol Biol.
2000;
299
551-572
- 36
Yagi T, Takeichi M.
Cadherin superfamily genes: functions, genomic organization, and neurologic diversity.
Genes & Dev.
2000;
14
1169-1180
- 37
Koch P J, Franke W W.
Desmosomal cadherins: another growing multigene family of adhesion molecules.
Curr Opin Cell Biol.
1994;
6
682-687
- 38
Dunne J, Hanby A M, Poulsom R, Jones T A, Sheer D, Chin W G, Da S M, Zhao Q, Beverley P C,
Owen M J.
Molecular cloning and tissue expression of FAT, the human homologue of the Drosophila
fat gene that is located on chromosome 4q34-q35 and encodes a putative adhesion molecule.
Genomics.
1995;
30
207-223
- 39
Sano K, Tanihara H, Heimark R L, Obata S, Davidson M, St John T, Taketani S, Suzuki S.
Protocadherins: a large family of cadherin-related molecules in central nervous system.
Embo J.
1993;
12
2249-2256
- 40
Wu Q, Maniatis T.
Large exons encoding multiple ectodomains are a characteristic feature of protocadherin
genes.
Proc Natl Acad Sci USA.
2000;
97
3124-3129
- 41
Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R, Watanabe M, Ishii H, Yasuda M, Mishina M,
Yagi T.
Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic
complex.
Neuron.
1998;
20
1137-1151
- 42
Senzaki K, Ogawa M, Yagi T.
Proteins of the CNR family are multiple receptors for Reelin.
Cell.
1999;
99
635-647
- 43
Del Rio J A, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S, Nakajima K,
Miyata T, Ogawa M, Mikoshiba K.
A role for Cajal-Retzius cells and reelin in the development of hippocampal connections.
Nature.
1997;
385
70-74
- 44
D'Arcangelo G, Miao G G, Chen S C, Soares H D, Morgan J I, Curran T.
A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.
Nature.
1995;
374
719-723
- 45
Impagnatiello F, Guidotti A R, Pesold C, Dwivedi Y, Caruncho H, Pisu M G, Uzunov D P,
Smalheiser N R, Davis J M, Pandey G N, Pappas G D, Tueting P, Sharma R P, Costa E.
A decrease of reelin expression as a putative vulnerability factor in schizophrenia.
Proc Natl Acad Sci U S A.
1998;
95
15 718-15 723
- 46
Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J, Fertitta A, Carrano A V,
Nagao M.
Human ret proto-oncogene mapped to chromosome 10q11.2.
Oncogene.
1989;
4
1519-1521
- 47
Formstone C J, Barclay J, Rees M, Little P F.
Chromosomal localization of Celsr2 and Celsr3 in the mouse; Celsr3 is a candidate
for the tippy (tip) lethal mutant on chromosome 9.
Mamm Genome.
2000;
11
392-394
- 48
Hadjantonakis A K, Formstone C J, Little P FR.
mCelsr1 is an evolutionarily conserved seven-pass transmembrane receptor and is expressed
during mouse embryonic development.
Mech Dev.
1998;
78
91-95
- 49
Hadjantonakis A K, Sheward W J, Harmar A J, de Galan L, Hoovers J M, Little P F.
Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor,
maps to mouse chromosome 15 and human chromosome 22qter.
Genomics.
1997;
45
97-104
- 50
Nakayama M, Nakajima D, Nagase T, Nomura N, Seki N, Ohara O.
Identification of high-molecular-weight proteins with multiple EGF-like motifs by
motif-trap screening.
Genomics.
1998;
51
27-34
- 51
Gao F B, Brenman J E, Jan L Y, Jan Y N.
Genes regulating dendritic outgrowth, branching, and routing in Drosophila.
Genes & Dev.
1999;
13
2549-2561
- 52
Usui T, Shima Y, Shimada Y, Hirano S, Burgess R W, Schwarz T L, Takeichi M, Uemura T.
Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under
the control of Frizzled.
Cell.
1999;
98
585-595
- 53
Coughlin S R.
Expanding horizons for receptors coupled to G proteins: diversity and disease.
Curr Opin Cell Biol.
1994;
6
191-197
- 54
Linder M E, Gilman A G.
G-Proteine.
Spektrum der Wissenschaft.
1992;
9
54-62
- 55
Dhanasekaran N, Tsim S T, Dermott J M, Onesime D.
Regulation of cell proliferation by G proteins.
Oncogene.
1998;
17
1383-1394
- 56
Gutkind J S.
Cell growth control by G protein-coupled receptors: from signal transduction to signal
integration.
Oncogene.
1998;
17
1331-1342
- 57
Lindsay E A, Morris M A, Gos A, Nestadt G, Wolyniec P S, Lasseter V K, Shprintzen R,
Antonarakis S E, Baldini A, Pulver A E.
Schizophrenia and chromosomal deletions within 22q11.2.
Am J Hum Genet.
1995;
56
1502-1503
- 58
Pulver A E, Karayiorgou M, Wolyniec P S, Lasseter V K, Kasch L, Nestadt G, Antonarakis S,
Housman D, Kazazian H H, Meyers D. et al .
Sequential strategy to identify a susceptibility gene for schizophrenia: report of
potential linkage on chromosome 22q12-q13.1: Part 1.
Am J Med Genet.
1994;
54
36-43
- 59
Pulver A E, Karayiorgou M, Lasseter V K, Wolyniec P, Kasch L, Antonarakis S, Housman D,
Kazazian H H, Meyers D, Nestadt G. et al .
Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1:
Part 2.
Am J Med Genet.
1994;
54
44-50
- 60
Stoeber G, Saar K, Rüschendorf F, Meyer J, Nürnberg G, Jatzke S, Franzek E, Reis A,
Lesch K-P, Wienker T F, Beckmann H.
Splitting schizophrenia: periodic catatonia- susceptibility locus on chromosome 15q15.
Am J Hum Genet.
2000;
67
1201-1207
- 61
Barden N, Morissette J.
Chromosome 13 workshop report.
Am J Med Genet.
1999;
88
260-262
- 62
Crowe R R, Vieland V.
Report of the Chromosome 5 Workshop of the Sixth World Congress on Psychiatric Genetics.
Am J Med Genet.
1999;
88
229-232
- 63
Riley B P, Lin M W, Mogudi-Carter M, Jenkins T, Williamson R, Powell J F, Collier D,
Murray R.
Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32
in southern African Bantu-speaking families.
Psychiatr Genet.
1998;
8
155-162
- 64
Schwab S G, Eckstein G N, Hallmayer J, Lerer B, Albus M, Borrmann M, Lichtermann D,
Ertl M A, Maier W, Wildenauer D B.
Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for
schizophrenia in German and Israeli families by multipoint affected sib-pair linkage
analysis.
Mol Psychiatry.
1997;
2
156-160
- 65
Van Broeckhoven C, Verheyen G.
Report of the chromosome 18 workshop.
Am J Med Genet.
1999;
88
263-270
- 66 Maier W, Schwab S, Rietschel M. Genetik funktioneller psychischer Störungen. In:
Möller HJ, ed., translator and editor Psychiatrie und Psychotherapie. Berlin Heidelberg
New York: Springer-Verlag 2000: 69-101
- 67 Leonhard K. Aufteilung der endogenen Psychosen und ihre differenzierte Ätiologie. Stuttgart
New York: Georg Thieme Verlag 1995
- 68
Nesslinger N J, Gorski J L, Kurczynski T W, Shapira S K, Siegel-Bartelt J, Dumanski J P,
Cullen Jr R F, French B N, McDermid H E.
Clinical, cytogenetic, and molecular characterization of seven patients with deletions
of chromosome 22q13.3.
Am J Hum Genet.
1994;
54
464-472
- 69
Gross J, Grimm O, Ortega G, Mössner R, Riederer P, Meyer J, Lesch K-P.
Allelic Variants of the human CELSR1 cadherin gene.
Eur Arch Psychiatry Clin Neurosci.
2000;
250
40
- 70
Gross J, Grimm O, Ortega G, Teuber I, Lesch K-P, Meyer J.
Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate
for catatonic schizophrenia in a large family.
Psychiatr Genet.
2001;
11
197-200
- 71
Teicher L S, Caspari E W.
The genetics of blind - a lethal factor in mice.
J Hered.
1978;
69
86-90
- 72
Watson M L.
Blind - a dominant mutation in mice.
J Hered.
1968;
59
60-64
Dr. J. Groß
Praxis für Psychiatrie und Psychotherapie
Münzstr. 10
97070 Würzburg
eMail: blocherundgross@tiscalinet.de
