UPF2 is a critical regulator of liver development, function and regeneration

TY - JOUR

T1 - UPF2 is a critical regulator of liver development, function and regeneration

AU - Thoren, Lina A

AU - Nørgaard, Gitte A

AU - Weischenfeldt, Joachim

AU - Waage, Johannes

AU - Jakobsen, Janus S

AU - Damgaard, Inge

AU - Bergström, Frida C

AU - Blom, Anna M

AU - Borup, Rehannah

AU - Bisgaard, Hanne Cathrine

AU - Porse, Bo T

PY - 2010/7/19

Y1 - 2010/7/19

N2 - Background: Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues. Methodology/Principal Findings: Here we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration. Conclusion/Significance: Collectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology.

AB - Background: Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues. Methodology/Principal Findings: Here we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration. Conclusion/Significance: Collectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology.

U2 - 10.1371/journal.pone.0011650

DO - 10.1371/journal.pone.0011650

M3 - Journal article

C2 - 20657840

SN - 1932-6203

VL - 5

SP - e11650

JO - PLoS ONE

JF - PLoS ONE

IS - 7

ER -