title: Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation.
abstract: OBJECTIVE
  Proliferating adult stem cells in the subgranular zone of the dentate gyrus have the capacity not only to divide, but also to differentiate into neurons and integrate into the hippocampal circuitry. The present study identifies several hippocampal genes putatively regulated by zinc and tests the hypothesis that zinc deficiency impairs neuronal stem cell differentiation.
  
  
  METHODS
  Genes that regulate neurogenic processes were identified using microarray analysis of hippocampal mRNA isolated from adult rats fed zinc-adequate or zinc-deficient (ZD) diets. We directly tested our hypothesis with cultured human neuronal precursor cells (NT2), stimulated to differentiate into post-mitotic neurons by retinoic acid (RA), along with immunocytochemistry and western analysis.
  
  
  RESULTS
  Microarray analysis revealed the regulation of genes involved in cellular proliferation. This analysis also identified a number of genes known to be involved in neuronal differentiation, including the nuclear RA receptor, retinoid X receptor (RXR), doublecortin, and a transforming growth factor-beta (TGF-β) binding protein (P < 0.05). Zinc deficiency significantly reduced RA-induced expression of the neuronal marker proteins doublecortin and β-tubulin type III (TuJ1) to 40% of control levels (P < 0.01). This impairment of differentiation may be partially mediated by alterations in TGF-β signaling. The TGF-β type II receptor, responsible for binding TGF-β during neuronal differentiation, was increased 14-fold in NT2 cells treated with RA (P < 0.001). However, this increase was decreased by 60% in ZD RA-treated cells (P < 0.001).
  
  
  CONCLUSIONS
  This research identifies target genes that are involved in governing neurogenesis under ZD conditions and suggests an important role for TGF-β and the trace metal zinc in regulating neuronal differentiation.
authors.affiliation: Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Gower-Winter
authors.forename: Rikki S
authors.initials: RS
authors.lastname: Corniola
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Morgan
authors.forename: Cathy W
authors.initials: CW
authors.lastname: Levenson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D055028:Comparative Genomic Hybridization; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D047488:Retinoid X Receptors / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014404:Tubulin / Q000235:genetics; D015032:Zinc / Q000172:deficiency*
chemical_list: C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D047488:Retinoid X Receptors; D014404:Tubulin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015032:Zinc