El paper del factor de transcripció Math6 en la diferenciació pancreàtica

Abstract

[cat]El pàncrees és una glándula secretora formada per teixit exocrí i endocrí. El compartiment endocrí està format per les cèl.lules alfa(productores de glucagó), les cèl.lules beta (productores d’insulina), les cèl.lules delta (somatostatina), les cèl.lules PP (polipèptid pancreàtic) i las cèl.lules epsilon (grelina). La Diabetis Mellitus és un grup de malalties metabòliques que es caracteritzent per mantenir nivells elevats de glucosa en sang com a resultat de la incapacitat de produir o utilitzar insulina. Actualment, el tractament de la diabetis es basa en injeccions periòdiques d’insulina. Per solucionar i millorar la vida d’aquests pacients hi ha molts grups que treballen per trobar nous fonts de cèl.lules productores d’insulina que puguin recuperar la massa de cèl.lules beta perduda durant la diabetis.

[eng] The bHLH transcription factor Neurogenin3 (Neurog3) initiates the endocrine differentiation program in the embryonic pancreas. We previously identified the bHLH factor Math6 as a component of the pancreatic transcriptional cascade downstream of Neurog3. Math6 is found in Neurog3+ endocrine progenitors and, mirroring Neurog3, is down-regulated in mature islet cells. While Math6 is essential for early embryonic development, the function of this factor during endocrine differentiation remains elusive. This thesis has aimed to gain insight into the molecular function of Math6 during the endocrine differentiation program initiated by Neurog3 in the pancreas. In the first objective we have done a biochemical characterization of the transcriptional activity of Math6, where the results have shown that it acts a transcriptional repressor. In the second objective, we have identified Math6’s target genes during the endocrine differentiation process using microarrays in a cellular model (mouse ductal cells). The study of global changes in the expression profile of these cells has allowed us to identify the cell cycle regulation as a potential function of Math6. All the data have been functionally corroborated, Math6 silencing inhibits the cellular proliferation and produces an increase in the number of cells in G2/M phases. We have also demonstrated that the deregulation of the cyclinB1/Cdk1 complex could be the cause of these changes along the cell cycle phase distribution. In the third objective, we have characterized the Math6 pancreas specific KO mice model during development and adulthood. At P1 stage (day of birth), we observe an increase in somatostatin cells but not in other endocrine cells, and the animal does not develop any functional phenotype. The gene expression profile at e14.5-15.5 (maxim endocrine expansion) shows a decrease in the expression of Neurog3, NeuroD1 and Nkx6.1, suggesting a delay in the activation of the endocrine differentiation program. In summary with this work we have demonstrated that Math6 possess a repressor transcriptional activity and we have defined that it has a weak role in the endocrine differentiation program. Moreover, these results uncover for the first time a potential function of Math6 as a regulator of cell cycle progression