Role of Pax6 in pancreatic endocrine cell subtype specification

Role of Pax6 in pancreatic endocrine cell subtype specification

Ahmad, Zeeshan

Dissertation

Angenommen am: 2013-05-17

Erschienen: 2014-03-27

Betreuer: Mansouri, Ahmed Prof. Dr.

Gutachter: Engel, Wolfgang Prof. Dr.

Gutachter: Dressel, Ralf Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0022-5E6E-C

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Zusammenfassung

Englisch

Pax6, a transcription factor from the paired box gene family is expressed in the endocrine pancreas and is required for its proper development. As Pax6 classical and pancreas-specific conditional knockout mice die early after birth, it is not possible to analyze the role of Pax6 in adult endocrine cell function. Therefore, we generated non-inducible alpha-cell-specific and inducible beta-cell-specific Pax6 knockout mice to observe the cell-type-specific effect of Pax6 ablation. Following Pax6 ablation, the adult beta-cells lost their mature differentiation state and function. This was evident by the reduced expression of insulin, MafA, Nkx6.1, Glut2, and GLP-1 receptor and an increased expression of proSAAS and 7B2. Loss of beta-cell function in turn resulted in hyperglycemia in these mice. Furthermore, these Pax6-deficient beta-cells started to express ghrelin and persisted in the islets as immature beta-cell-like cells. Ablation of Pax6 from alpha-cells also resulted in the loss of mature alpha-cell function that was evident by the reduced expression of glucagon and MafB and an increased expression of 7B2. Pax6-deficient alpha-cells also started to express ghrelin. In this study, we confirmed the essential requirement of Pax6 in adult alpha- and beta-cell function in vivo and clearly established the origin of ghrelin+ cells in the respective Pax6 knockout pancreata. Moreover, when overexpressed in the pancreas, Pax6 did not affect the development or function of beta-cells but the numbers of alpha-, PP-, and epsilon-cells were slightly reduced.

Keywords: Pancreas; Endocrine; Pax6; Insulin; Glucagon; Ghrelin