Using a conditional deletion of the Hnf1b gene in mouse pancreatic cells, a study led by Cécile Haumaitre¹ demonstrates the role of Hnf1b in pancreas development. The results are published in Development².

There are different types of diabetes. The Maturity-Onset Diabetes of the Young, known as MODY 5, is associated with mutations in the human Hnf1b gene, which codes for a transcription factor expressed in pancreatic cells during embryogenesis.

To better understand the role of Hnf1b during pancreas development, the team led by Cécile Haumaitre¹ analyzed the effects of a constitutive and inducible conditional inactivation of Hnf1b at key developmental stages in mouse pancreatic cells. The results are published in Development.

The researchers have shown that Hnf1b plays a major role in pancreas development and is essential to maintain the identity of exocrine cells – which secrete digestive enzymes – and to ensure endocrine functions – production of hormones that regulate blood sugar. When Hnf1b is deleted, exocrine cells are disorganized and dysfunctional, and endocrine cells are missing. This study demonstrates the importance of Hnf1b in pancreas formation. It also has allowed identification of new genes regulated by Hnf1b, such as Glis3, which is involved in duct formation and in the regulation of pancreatic endocrine cells. These results could explain the development of MODY5 diabetes as a deregulation of Ngn3 expression leading to a decrease in insulin-producing ß cells.

This work may help design new targets and therapeutic protocols to treat diabetes. Furthermore, pancreatic cancer, which is due to a dysfunction of exocrine cells, could originate from reactivation of embryonic signals. It is therefore essential to identify these signals during development.

1. Genetic and epigenetic regulation of pancreas development - UMR 7622-Developmental Biology Laboratory (CNRS-UPMC-Inserm)

2. Hnf1b controls pancreas morphogenesis and generation of Ngn3+ endocrine progenitors. De Vas MG, Kopp JL, Heliot C, Sander M, Cereghini S, Haumaitre C. Development. (2015) 142(5):871-82. doi: 10.1242/dev.110759.

Figure: Cross-section of the pancreas from mouse embryonic day E16.5, control (A, C, E) or after Hnf1b deletion (B, D, F). Hnf1b gene deletion is associated with a global disorganization of the pancreas (A, B) and of acinar cells (green: C, D), an absence of Ngn3 expressing cells (red: C, D), and a lack of endocrine cells, demonstrated by loss of insulin and glucagon expressing cells (red and green respectively: E, F).