title: A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration.
abstract: The liver harbors a distinct capacity for endogenous regeneration; however, liver regeneration is often impaired in disease and therefore insufficient to compensate for the loss of hepatocytes and organ function. Here we describe a functional genetic approach for the identification of gene targets that can be exploited to increase the regenerative capacity of hepatocytes. Pools of small hairpin RNAs (shRNAs) were directly and stably delivered into mouse livers to screen for genes modulating liver regeneration. Our studies identify the dual-specific kinase MKK4 as a master regulator of liver regeneration. MKK4 silencing robustly increased the regenerative capacity of hepatocytes in mouse models of liver regeneration and acute and chronic liver failure. Mechanistically, induction of MKK7 and a JNK1-dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing.
authors.affiliation: Department of Gastroenterology, Hepatology & Endocrinology, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Marina
authors.initials: M
authors.lastname: Pesic
authors.forename: Ramona
authors.initials: R
authors.lastname: Rudalska
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kang
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.forename: Florian
authors.initials: F
authors.lastname: Heinzmann
authors.forename: Lisa
authors.initials: L
authors.lastname: Hoenicke
authors.forename: Anja
authors.initials: A
authors.lastname: Hohmeyer
authors.forename: Anna
authors.initials: A
authors.lastname: Potapova
authors.forename: Ina
authors.initials: I
authors.lastname: Rittelmeier
authors.forename: Michael
authors.initials: M
authors.lastname: Jarek
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Maren
authors.initials: M
authors.lastname: Scharfe
authors.forename: Frank
authors.initials: F
authors.lastname: Klawonn
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D004251:DNA Transposable Elements; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000293:injuries / Q000473:pathology / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D004251:DNA Transposable Elements; D034741:RNA, Small Interfering; D048670:MAP Kinase Kinase 4; D006867:Hydrolases; C020156:fumarylacetoacetase