Novel role of Rfx6 gene in insulin secretion
Islet of Langerhans of an adult mice pancreas showing the expression of Rfx6 transcription factor (red) in the beta cells nuclei (marked by the insulin, green)
Dec. 12, 2014
For the first time, the team of Gérard Gradwohl, Inserm research leader at the Institute of Genetics and Molecular and Cellular Biology of Illkirch (IGBMC / Inserm-CNRS-Université of Strasbourg) shows that Rfx6 gene is essential for pancreatic beta cell function. In adult mice, this gene turns out to be important for the secretion of insulin as well as for the maintenance of beta cell identity.
These results are published December 11th in Cell Reports.
Since 2010, the scientists knew that Rfx6 gene has a key-role in the formation of beta cells which produce insulin. Mice lacking this gene die shortly after birth due to severe diabetes. Whereas human newborn children presenting Rfx6 mutations have neonatal diabetes and are treated with insulin.
From a factor involved in neonatal diabetes, Rfx6 is now also seen as a gene having a key role in the control of insulin secretion and thus potentially involved in the development of diabetes in the adult.
Indeed, the researchers of the IGBMC created mice models in which mature beta-cells were modified to inactivate Rfx6 gene. As a result these mice are intolerant to glucose (prediabetes).
Why? The explanation is that several crucial steps regulating glucose induced insulin secretion are perturbed if Rfx6 is not expressed in beta-cells: glucose detection, electric activity of beta cells and calcium ions influx. Rfx6 actually regulates directly the expression of key genes controlling these processes. This cascade of events are key for appropriate insulin secretion in response to fluctuating glycaemia, their alteration leads to defective insulin secretion.
Even more surprising, by studying the transcriptome of the mutant mice (without Rfx6), Gérard Gradwohl's team discovered that genes which are normally repressed in mature beta-cells become active: these genes also called "disallowed" or “forbidden” instead of remaining silent are now expressed thus leading to the loss of identity of mature beta cells. In a way they undergo a dedifferentiation process and "forget" their beta cell traits.
INSERM Press release (in French):