Format

Send to

Choose Destination
PLoS One. 2016 Mar 14;11(3):e0150997. doi: 10.1371/journal.pone.0150997. eCollection 2016.

Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum.

Canal F1,2,3,4, Charawi S1,2,3,4, Grimber G1,2,3,4, Houbron C1,2,3, Drouet V1,2,3,4, Colnot S1,2,3,4, Terris B1,2,3,4,5, Cavard C1,2,3,4, Perret C1,2,3,4.

Author information

1
Inserm, U1016, Institut Cochin, 75014 Paris, France.
2
Cnrs, UMR8104, 75014 Paris, France.
3
Université Paris Descartes, 75014 Paris, France.
4
Equipe labellisée LNCC, Paris, France.
5
Pathology Unit, Hôpital Cochin, 75014 Paris, France.

Abstract

BACKGROUND:

Fine tuning of the Wnt/β-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/β-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/β-catenin signaling in several animal models and the Wnt/β-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/β-catenin signaling during the adult stage.

METHODOLOGY/PRINCIPAL FINDINGS:

We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/β-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders.

CONCLUSION:

We show that Notum is not a key actor of Wnt/β-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes.

PMID:
26974334
PMCID:
PMC4790944
DOI:
10.1371/journal.pone.0150997
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center