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Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2‐dependent cyclin E expression
Author(s) -
Rabaneda Luis G.,
Carrasco Manuel,
LópezToledano Miguel A.,
MurilloCarretero Maribel,
Ruiz Félix A.,
Estrada Carmen,
Castro Carmen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-109306
Subject(s) - neurogenesis , subventricular zone , neuroblast , biology , dentate gyrus , basic fibroblast growth factor , neural stem cell , progenitor cell , microbiology and biotechnology , fibroblast growth factor , hippocampus , endocrinology , neuroscience , medicine , growth factor , stem cell , biochemistry , receptor
Hyperhomocysteinemia (HHcy)—abnormally elevated plasma levels of homocysteine (Hcy)—has been associated with the development of neurodegenerative dementia and mild cognitive impairment. This association suggests that HHcy might facilitate memory loss in the elderly. As memory loss can occur through a deteriorated neurogenic capacity, we have studied the effects of Hcy on neural progenitor cells (NPCs) both in vitro and in vivo . We show that Hcy exerts an antiproliferative effect on basic fibroblast growth factor (bFGF) ‐stimulated NPCs isolated from the postnatal subventricular zone (SVZ), accompanied by inactivation of the extracellular signal‐regulated kinase (Erk1/2) and inhibition of Erk1/ 2‐dependent expression of cyclin E. Using a mice model we show that, under normal folate conditions, HHcy exerts an inhibitory effect on adult brain neurogenesis. This inhibition occurs in the caudal areas of the dentate gyrus (DG) of the hippocampus, a neurogenic area mainly involved in learning and memory performance, and in the SVZ, recently implicated in olfactory learning performance. In both areas reduced number of proliferative neuroblasts were found. Since neuroblasts are primarily bFGF‐responsive progenitors already committed to a neuronal phenotype, our results strongly suggest that excess Hcyinhibits neurogenesis in the DG and SVZ byinhibiting the bFGF‐dependent activation of Erk1/2 in these cells.— Rabaneda, L. G., Carrasco, M., Lopez‐Toledano, M. A., Murillo‐Carretero, M., Ruiz, F. A., Estrada, C., Castro, C. Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2‐dependent cyclin E expression. FASEB J. 22, 3823–3835 (2008)