Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders.
A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. The reduced expression is due to a duplicon-based genomic rearrangement event resulting in an Aph-1b dosage imbalance. The expression levels of the other gamma-secretase components were not affected. However, gamma-secretase cleavage activity was significantly changed, and the APO-SUS/-UNSUS Aph-1b genotypes segregated with a number of behavioral phenotypes. Thus, a subtle imbalance in the expression of a single, developmentally important protein may be sufficient to cause a complex phenotype.
Coolen
Marcel W
MW
Department of Molecular Animal Physiology, Nijmegen Center for Molecular Life Sciences, Institute for Neuroscience, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands.
Van Loo
Karen M J
KM
Van Bakel
Nick N H M
NN
Pulford
David J
DJ
Serneels
Lutgarde
L
De Strooper
Bart
B
Ellenbroek
Bart A
BA
Cools
Alexander R
AR
Martens
Gerard J M
GJ
D053829:Amyloid Precursor Protein Secretases; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D001522:Behavior, Animal; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010447:Peptide Hydrolases; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects
D008565:Membrane Proteins; D012333:RNA, Messenger; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D001058:Apomorphine