OBJECTIVES: 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). DISCUSSION: 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.
OBJECTIVES: 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). DISCUSSION: 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: Ina Tesseur; Kun Zou; Luke Esposito; Frederique Bard; Elisabeth Berber; Judith Van Can; Amy H Lin; Leslie Crews; Patrick Tremblay; Paul Mathews; Lennart Mucke; Eliezer Masliah; Tony Wyss-Coray Journal: J Clin Invest Date: 2006-11 Impact factor: 14.808
Authors: Panagiotis K Politis; Georgia Makri; Dimitra Thomaidou; Markus Geissen; Hermann Rohrer; Rebecca Matsas Journal: Proc Natl Acad Sci U S A Date: 2007-10-30 Impact factor: 11.205
Authors: Julieta G Mendoza-Torreblanca; Eduardo Martínez-Martínez; Miguel Tapia-Rodríguez; Rogelio Ramírez-Hernández; Gabriel Gutiérrez-Ospina Journal: Neurosci Res Date: 2007-12-08 Impact factor: 3.304
Authors: Sung Min Nam; Jong Whi Kim; Hyun Jung Kwon; Dae Young Yoo; Hyo Young Jung; Dae Won Kim; In Koo Hwang; Je Kyung Seong; Yeo Sung Yoon Journal: Neurochem Res Date: 2017-08-02 Impact factor: 3.996
Authors: Stefanie Pfaender; Karl Föhr; Anne-Kathrin Lutz; Stefan Putz; Kevin Achberger; Leonhard Linta; Stefan Liebau; Tobias M Boeckers; Andreas M Grabrucker Journal: Neural Plast Date: 2016-05-09 Impact factor: 3.599
Authors: Mi-Young Moon; Hyun Jung Kim; Bo Young Choi; Min Sohn; Tae Nyoung Chung; Sang Won Suh Journal: Stem Cells Int Date: 2018-04-18 Impact factor: 5.443