title: AP2α transcriptional activity is essential for retinoid-induced neuronal differentiation of mesenchymal stem cells.
abstract: Pre-activation of the retinoid signaling pathway by all-trans retinoic acid facilitates neuronal differentiation of mesenchymal stem cells. Using protein/DNA based screening assays, we identified activator protein 2α as an important downstream target of all-trans retinoic acid. Although all-trans retinoic acid treatment significantly increased activator protein 2α transcriptional activity, it did not affect its expression. Inhibition of activator protein 2α with dominant-negative mutants reduced ATRA-induced differentiation of mesenchymal stem cells into neurons and reversed its associated functional recovery of memory impairment in the cell-based treatment of a hypoxic-ischemic brain damage rat model. Dominant-negative mutants of activator protein 2α inhibited the expression of neuronal markers which were induced by retinoic acid receptor β activation. All-trans retinoic acid treatment increased phosphorylation of activator protein 2α and resulted in its nuclear translocation. This was blocked by siRNA-mediated knockdown of retinoic acid receptor β. Furthermore, we found that retinoic acid receptor β directly interacted with activator protein 2α. In summary, the regulation of all-trans retinoic acid on activator protein 2α transcriptional activity was mediated by activation of retinoic acid receptor β and subsequent phosphorylation and nuclear translocation of activator protein 2α. Our results strongly suggest that activator protein 2α transcriptional activity is essential for all-trans retinoic acid-induced neuronal differentiation of mesenchymal stem cells.
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gong
authors.affiliation: Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Nan
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wei
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Youxue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China. Electronic address: Jiechen010@gmail.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Nutritional Research Center, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Center, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Collaboration Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China. Electronic address: tyli@vip.sina.com.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D050656:Transcription Factor AP-2; D014212:Tretinoin
keywords: AP2α; ATRA; Activator protein 2α; All-trans retinoic acid; GFAP; GLuc; Gaussia luciferase; MAP-2; MNM; MSC; Mesenchymal stem cells; NSE; Neurodifferentiation; RAR; Retinoic acid receptor β; Tuj1; activator protein 2α; all-trans retinoic acid; deleted TAD domain; deleted bHLH domain; dnAP2α; dominant negative deletion mutants of AP2α; glial fibrillary acidic protein; mesenchymal stem cells; microtubule-associated protein-2; modified neuronal induction medium; neuron specific enolase; neuron-specific class III beta-tubulin; retinoic acid receptor; ΔTAD; ΔbHLH