title: Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin-Lowry syndrome.
abstract: Coffin-Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1-4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal-regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons than in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P-ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element binding and Ets LiKe gene1 show over-activation in RSK2-deficient neurons. Finally, c-Fos, Zif268 and Arc were significantly over-expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin-Lowry syndrome.
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Schneider
authors.forename: Tahir
authors.initials: T
authors.lastname: Mehmood
authors.forename: Solange
authors.initials: S
authors.lastname: Pannetier
authors.forename: André
authors.initials: A
authors.lastname: Hanauer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D038921:Coffin-Lowry Syndrome / Q000201:enzymology / Q000235:genetics*; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D006624:Hippocampus / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3