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

Area of Science:

• Endocrinology
• Molecular Biology
• Developmental Biology

Background:

• Hedgehog (Hh) signaling is crucial for pancreas development.
• The role of Hh pathway overactivation in adult pancreatic beta cells in vivo remains largely unexplored.

Purpose of the Study:

• To investigate the functional consequences of upregulated Hh signaling in adult beta cells.
• To determine the impact of GLI2 activation in primary cilia-deficient beta cells.

Main Methods:

• Generated transgenic mice with activated GLI2 in primary cilia-deficient beta cells.
• Assessed beta cell function, insulin secretion, and glucose tolerance.
• Analyzed gene expression of beta cell markers, transcription factors, and Hh pathway targets.

Main Results:

• Hh pathway upregulation impaired beta cell function and insulin secretion, causing glucose intolerance.
• Reduced expression of mature beta cell genes and transcription factors was observed.
• Increased expression of precursor cell markers (Hes1, Sox9) and development of pancreatic tumors occurred with sustained Hh signaling.

Conclusions:

• Deregulation of the Hh pathway disrupts mature beta cell differentiation and function.
• Transient Hh activation allows for recovery of beta cell phenotype and normoglycemia.
• Sustained Hh signaling can lead to loss of beta cell identity and tumorigenesis.