Early-life iron deficiency anemia alters neurotrophic factor expression and hippocampal neuron differentiation in male rats.
Fetal-neonatal iron deficiency alters hippocampal neuronal morphology, reduces its volume, and is associated with acute and long-term learning impairments. However, neither the effects of early-life iron deficiency anemia on growth, differentiation, and survival of hippocampal neurons nor regulation of the neurotrophic factors that mediate these processes has been investigated. We compared hippocampal expression of neurotrophic factors in male rats made iron deficient (ID) from gestational d 2 to postnatal d (P) 7 to iron-sufficient controls at P7, 15, and 30 with quantitative RT-PCR, Western analysis, and immunohistology. Iron deficiency downregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus without compensatory upregulation of its specific receptor, tyrosine-receptor kinase B. Consistent with low overall BDNF activity, we found lower expression of early-growth response gene-1 and -2, transcriptional targets of BDNF signaling. Doublecortin expression, a marker of differentiating neurons, was reduced during peak iron deficiency, suggesting impaired neuronal differentiation in the ID hippocampus. In contrast, iron deficiency upregulated hippocampal nerve growth factor, epidermal growth factor, and glial-derived neurotrophic factor accompanied by an increase in neurotrophic receptor p75 expression. Our findings suggest that fetal-neonatal iron deficiency lowers BDNF function and impairs neuronal differentiation in the hippocampus.
Tran
Phu V
PV
Department of Pediatrics, Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN 55455, USA.
Carlson
Erik S
ES
Fretham
Stephanie J B
SJ
Georgieff
Michael K
MK
D018798:Anemia, Iron-Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051766:Early Growth Response Protein 1 / Q000235:genetics; D051767:Early Growth Response Protein 2 / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486110:Egr1 protein, rat; C497328:Egr2 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D004815:Epidermal Growth Factor