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Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation.
Biochim Biophys Acta. 2016 12; 1863(12):3015-3026.BB

Abstract

Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway. Both elevated concentrations of Hcy and methyltransferase activity inhibition induced Spry2 promoter demethylation in NPC cultures leading to a sustained upregulation of the expression of Spry2 mRNA and protein. In addition, protein levels of two kinases responsible for Spry2 activation/deactivation were altered by Hcy: Spry2 kinase Dyrk1A levels diminished while Spry2 phosphatase PP2A increased, leading to changes in the phosphorylation pattern, activity and stability of Spry2. In conclusion, Hcy inhibits NPC proliferation by indirect mechanisms involving alterations in DNA methylation, gene expression, and Spry2 function, causing FGFR signaling impairment.

Authors+Show Affiliations

Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain; Currently at Laboratorio de Neurobiología Celular, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.Departamento de Anatomía, Facultad de Medicina, Universidad de Cádiz, Spain.Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain. Electronic address: carmen.castro@uca.es.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27686255

Citation

Rabaneda, Luis G., et al. "Altered Regulation of the Spry2/Dyrk1A/PP2A Triad By Homocysteine Impairs Neural Progenitor Cell Proliferation." Biochimica Et Biophysica Acta, vol. 1863, no. 12, 2016, pp. 3015-3026.
Rabaneda LG, Geribaldi-Doldán N, Murillo-Carretero M, et al. Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation. Biochim Biophys Acta. 2016;1863(12):3015-3026.
Rabaneda, L. G., Geribaldi-Doldán, N., Murillo-Carretero, M., Carrasco, M., Martínez-Salas, J. M., Verástegui, C., & Castro, C. (2016). Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation. Biochimica Et Biophysica Acta, 1863(12), 3015-3026. https://doi.org/10.1016/j.bbamcr.2016.09.018
Rabaneda LG, et al. Altered Regulation of the Spry2/Dyrk1A/PP2A Triad By Homocysteine Impairs Neural Progenitor Cell Proliferation. Biochim Biophys Acta. 2016;1863(12):3015-3026. PubMed PMID: 27686255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation. AU - Rabaneda,Luis G, AU - Geribaldi-Doldán,Noelia, AU - Murillo-Carretero,Maribel, AU - Carrasco,Manuel, AU - Martínez-Salas,José M, AU - Verástegui,Cristina, AU - Castro,Carmen, Y1 - 2016/09/26/ PY - 2016/03/22/received PY - 2016/09/13/revised PY - 2016/09/22/accepted PY - 2016/11/5/pubmed PY - 2017/10/5/medline PY - 2016/10/1/entrez KW - Dyrk1A KW - PP2A KW - Spry2 KW - homocysteine KW - neural progenitor cells KW - neurogenesis SP - 3015 EP - 3026 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1863 IS - 12 N2 - Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway. Both elevated concentrations of Hcy and methyltransferase activity inhibition induced Spry2 promoter demethylation in NPC cultures leading to a sustained upregulation of the expression of Spry2 mRNA and protein. In addition, protein levels of two kinases responsible for Spry2 activation/deactivation were altered by Hcy: Spry2 kinase Dyrk1A levels diminished while Spry2 phosphatase PP2A increased, leading to changes in the phosphorylation pattern, activity and stability of Spry2. In conclusion, Hcy inhibits NPC proliferation by indirect mechanisms involving alterations in DNA methylation, gene expression, and Spry2 function, causing FGFR signaling impairment. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/27686255/Altered_regulation_of_the_Spry2/Dyrk1A/PP2A_triad_by_homocysteine_impairs_neural_progenitor_cell_proliferation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-4889(16)30247-6 DB - PRIME DP - Unbound Medicine ER -