title: Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice.
abstract: Hyperphosphorylation of the microtubule binding protein Tau is a feature of a number of neurodegenerative diseases, including Alzheimer's disease. Tau is hyperphosphorylated in the hippocampus of dab1-null mice in a strain-dependent manner; however, it has not been clear if the Tau phosphorylation phenotype is a secondary effect of the morbidity of these mutants. The dab1 gene encodes a docking protein that is required for normal brain lamination and dendritogenesis as part of the Reelin signaling pathway. We show that dab1 gene inactivation after brain development leads to Tau hyperphosphorylation in anatomically normal mice. Genomic regions that regulate the phospho Tau phenotype in dab1 mutants have previously been identified. Using a microarray gene expression comparison between dab1-mutants from the high-phospho Tau expressing and low-phospho Tau expressing strains, we identified Stk25 as a differentially expressed modifier of dab1-mutant phenotypes. Stk25 knockdown reduces Tau phosphorylation in embryonic neurons. Furthermore, Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1. This work provides insights into the complex regulation of neuronal behavior during brain development and provides insights into the molecular cascades that regulate Tau phosphorylation.
authors.affiliation: Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuki
authors.forename: Mariam
authors.initials: M
authors.lastname: Zaka
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Marcel P
authors.initials: MP
authors.lastname: van der Brug
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Brian W
authors.initials: BW
authors.lastname: Howell
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D060045:Genes, Modifier / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000091042:Reelin Protein; D014443:Tyrosine; D016875:tau Proteins; C103773:Dab1 protein, mouse; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse