Study of intramembrane protease IMP1 related to presenilins in knockout mice model
Grigorenko A.P., Andreeva T.V., Gusev F.E., Rogaev E.I.
1 Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, RAS, Novosibirsk, Russia
2 Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
3 Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, USA
Mutations in intramembrane protease genes PSEN1 and PSEN2 are major genetics factors causing the development of familial early onset Alzheimer's Disease. Here we present the functional study of family of genes related to presenilins, termed IMPAS (IMP/SPP/PSH), previously identified in our laboratory. We generated the first knock-out mice for IMP1(H13/SPP)-/- gene. We found that loss-of function of IMP1 leads to severe central neural system (CNS) defects. Imp1-/- knockout mice was characterized by neural tube defects and cranial nerve and skeletal malformations. We performed a comprehensive study of molecular pathways differentially regulated in IMP1 knockout and control animals using high-through-put whole genome ChIP- seq and gene expression analysis, in-situ hybridization, Western immunoblotting , 2D gel-protein electrophoresis and luciferease reporter assays. The data revealed that a set of canonical signaling pathways essential in CNS development are not the primary targets for IMP1 aspartic transmembrane protease, and revealed the putative downstream molecular elements regulated by IMP1 in early development.
The authors were supported, in part, by NIH/NIA R01 AG029360 and by the Government of the Russian Federation (No 14.B25.31.0033).