title: Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ.
abstract: The seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Guoxi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xunde
authors.initials: X
authors.lastname: Xian
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Institute of Cardiovascular Sciences, Peking University, Beijing 100191, China lingchen@njmu.edu.cn georgeliu@bjmu.edu.cn.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China Department of Physiology, Nanjing Medical University, Nanjing 210029, China lingchen@njmu.edu.cn georgeliu@bjmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D060508:Wnt3 Protein / Q000378:metabolism
chemical_list: C115783:Bscl2 protein, mouse; D019925:Cyclin A; D044388:GTP-Binding Protein gamma Subunits; D047495:PPAR gamma; D060508:Wnt3 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020962:Heterotrimeric GTP-Binding Proteins
keywords: BSCL2; Cell proliferation; Differentiation of progenitor cells; Neurogenesis; Peroxisome proliferator-activated receptor gamma (PPARγ); Seipin