Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation.
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.
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.
Luis G
LG
Rabaneda
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.
Noelia
N
Geribaldi-Doldán
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.
Maribel
M
Murillo-Carretero
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.
Manuel
M
Carrasco
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain.
José M
JM
Martínez-Salas
Departamento de Anatomía, Facultad de Medicina, Universidad de Cádiz, Spain.
Cristina
C
Verástegui
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Spain. Electronic address: carmen.castro@uca.es.
Carmen
C
Castro
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000097603:Dyrk Kinases
D019927:Cyclin E; D006710:Homocysteine; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D000097603:Dyrk Kinases; C118389:Spry2 protein, mouse; C535148:Mapk1 protein, mouse
Dyrk1A; PP2A; Spry2; homocysteine; neural progenitor cells; neurogenesis