Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype.
Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about gamma-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in gamma-secretase cleavage activity towards one of its best-known substrates, the amyloid-beta precursor protein APP. We conclude that the low levels of Aph-1b mRNA and gamma-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.
Coolen
M W
MW
Department of Molecular Animal Physiology, Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University, Nijmegen, The Netherlands.
van Loo
K M J
KM
Ellenbroek
B A
BA
Cools
A R
AR
Martens
G J M
GJ
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity
C508903:Aph-1 protein, rat; D008565:Membrane Proteins; D012333:RNA, Messenger