Progesterone increases rat neural progenitor cell cycle gene expression and proliferation via extracellularly regulated kinase and progesterone receptor membrane components 1 and 2.
Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G(0)/G(1) phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK(1/2) inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.
Program in Neuroscience, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, California 90089, USA.
Lifei
L
Liu
Junming
J
Wang
Liqin
L
Zhao
Jon
J
Nilsen
Kelsey
K
McClure
Karren
K
Wong
Roberta Diaz
RD
Brinton
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D018891:Dentate Gyrus / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects*; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D011980:Receptors, Progesterone / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C486424:Pgrmc1 protein, rat; C541979:Pgrmc2 protein, rat; D011980:Receptors, Progesterone; D011374:Progesterone; D048049:Extracellular Signal-Regulated MAP Kinases