1. Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin-Lowry syndrome
- Author
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Tahir Mehmood, André Hanauer, Solange Pannetier, and Anne Schneider
- Subjects
MAPK/ERK pathway ,Coffin–Lowry syndrome ,Arc (protein) ,biology ,Kinase ,Glutamate receptor ,CREB ,medicine.disease ,Biochemistry ,Cell biology ,Ribosomal s6 kinase ,Cellular and Molecular Neuroscience ,biology.protein ,medicine ,CAMP response element binding - Abstract
J. Neurochem. (2011) 119, 447–459. 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.
- Published
- 2011