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Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice.

Abstract：

:Although Hedgehog (Hh) signaling regulates cell differentiation during pancreas organogenesis, the consequences of pathway up-regulation in adult β-cells in vivo have not been investigated. Here, we elevate Hh signaling in β-cells by expressing an active version of the GLI2 transcription factor, a mediator of the Hh pathway, in β-cells that are also devoid of primary cilia, a critical regulator of Hh activity. We show that increased Hh signaling leads to impaired β-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. This phenotype was accompanied by reduced expression of both genes critical for β-cell function and transcription factors associated with their mature phenotype. Increased Hh signaling further correlated with increased expression of the precursor cell markers Hes1 and Sox9, both direct Hh targets that are normally excluded from β-cells. Over time, the majority of β-cells down-regulated GLI2 levels, thereby regaining the full differentiation state and restoring normoglycemia in transgenic mice. However, sustained high Hh levels in some insulin-producing cells further eroded the β-cell identity and eventually led to the development of undifferentiated pancreatic tumors. Summarily, our results indicate that deregulation of the Hh pathway impairs β-cell function by interfering with the mature β-cell differentiation state.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Landsman L,Parent A,Hebrok M

doi

10.1073/pnas.1105404108

subject

Has Abstract

pub_date

2011-10-11 00:00:00

pages

17010-5

issue

41

eissn

0027-8424

issn

1091-6490

pii

1105404108

journal_volume

108

pub_type

杂志文章

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