A Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration | Zendy

Torsten Wüestefeld | Zendy; Marina Pešić | Zendy; Ramona Rudalska | Zendy; Daniel Dauch | Zendy; Thomas Longerich | Zendy; Tae-Won Kang | Zendy; Tetyana Yevsa | Zendy; Florian Heinzmann | Zendy; Lisa Hoenicke | Zendy; Anja Hohmeyer | Zendy; Anna Potapova | Zendy; Ina Rittelmeier | Zendy; Michael Jarek | Zendy; Robert Geffers | Zendy; Maren Scharfe | Zendy; Frank Klawonn | Zendy; Peter Schirmacher | Zendy; Nisar P. Malek | Zendy; Michael Ott | Zendy; Alfred Nordheim | Zendy; Arndt Vogel | Zendy; Michael P. Manns | Zendy; Lars Zender | Zendy

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A Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration

Author(s) -

Torsten Wüestefeld,

Marina Pešić,

Ramona Rudalska,

Daniel Dauch,

Thomas Longerich,

Tae-Won Kang,

Tetyana Yevsa,

Florian Heinzmann,

Lisa Hoenicke,

Anja Hohmeyer,

Anna Potapova,

Ina Rittelmeier,

Michael Jarek,

Robert Geffers,

Maren Scharfe,

Frank Klawonn,

Peter Schirmacher,

Nisar P. Malek,

Michael Ott,

Alfred Nordheim,

Arndt Vogel,

Michael P. Manns,

Lars Zender

Publication year - 2013

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2013.03.026

Subject(s) - biology , gene silencing , regeneration (biology) , liver regeneration , microbiology and biotechnology , transcription factor , regulator , rna interference , ap 1 transcription factor , small hairpin rna , gene , genetics , rna

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.

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