title: The Ras-ERK MAPK regulatory network controls dedifferentiation in Caenorhabditis elegans germline.
abstract: How a committed cell can be reverted to an undifferentiated state is a central question in stem cell biology. This process, called dedifferentiation, is likely to be important for replacing stem cells as they age or get damaged. Tremendous progress has been made in understanding this fundamental process, but its mechanisms are poorly understood. Here we demonstrate that the aberrant activation of Ras-ERK MAPK signaling promotes cellular dedifferentiation in the Caenorhabditis elegans germline. To activate signaling, we removed two negative regulators, the PUF-8 RNA-binding protein and LIP-1 dual specificity phosphatase. The removal of both of these two regulators caused secondary spermatocytes to dedifferentiate and begin mitotic divisions. Interestingly, reduction of Ras-ERK MAPK signaling, either by mutation or chemical inhibition, blocked the initiation of dedifferentiation. By RNAi screening, we identified RSKN-1/P90(RSK) as a downstream effector of MPK-1/ERK that is critical for dedifferentiation: rskn-1 RNAi suppressed spermatocyte dedifferentiation and instead induced meiotic divisions. These regulators are broadly conserved, suggesting that similar molecular circuitry may control cellular dedifferentiation in other organisms, including humans.
authors: Division of Hematology/Oncology, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors: Dong Seok
authors: DS
authors: Cha
authors: Udaya Sree
authors: US
authors: Datla
authors: Sarah E
authors: SE
authors: Hollis
authors: Judith
authors: J
authors: Kimble
authors: Myon-Hee
authors: MH
authors: Lee
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D054337:Cell Dedifferentiation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005854:Germ Cells / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000473:pathology; D021381:Protein Transport; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D013090:Spermatocytes / Q000201:enzymology / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; C085697:mpk-1 protein, C elegans; D018631:ras Proteins