PgmNr M5095: Systemic metabolic effects exerted by a point mutation in the RED subdomain of PAX6.

Authors:
N. F. Chhabra 1,2 ; M. Wu 1,2 ; M. Fütterer 1,2 ; I. Irmler 1,2 ; J. Beckers 1,2,3 ; M. Götz 4,5 ; J. Rozman 1,2 ; G. Przemeck 1,2 ; M. Hrabe de Angelis 1,2,3


Institutes
1) Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 2) German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; 3) Chair of Experimental Genetics, Centre of Life and Food Sciences, Weihenstephan, Technische Universität München, Freising, Germany; 4) Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany; 5) Physiological Genomics, Institute of Physiology, Munich University, Munich, Germany.


Abstract:

The paired box protein 6 (PAX6) is a major transcription factor involved in eye development. Additionally, its role in the development of the pancreas has previously been documented, although the underlying mechanisms in the homeostasis of the adult pancreas remain largely unknown.

The ENU-generated C3;CAnN-Pax6Leca2 mouse line with a point mutation (R128C) in the RED subdomain of the PAX6 protein, recapitulates a human mutation causing foveal hypoplasia. In addition to the retinal defects, the mutation translates into numerous observable abnormalities in the pancreas. Progressive islet distortion was discernable from the age of 4 weeks including various dysregulated genes. More specifically, up-regulation of the endocrinal progenitor marker Neurog3 and down-regulation of several β-cell specific markers in addition to increased proliferation within the islet suggested the prevailing phenotype to be most consistent with β-cell dedifferentiation.

Moreover, glucose stimulation of isolated islets in vitro and an intraperitoneal glucose challenge in vivo indicated reduced insulin content and secretion. However, this reduction was accompanied by a decreased fasting blood glucose level and a normal glucose clearance, possibly explained through the evident increased insulin sensitivity and decreased hepatic glucose production. Additionally, increase in locomotor activity and energy expenditure indicated an effect mediated via the hypothalamus, as an effect of the mutation. Taken together, the data suggests, as yet, unknown systemic function of PAX6 affecting the overall metabolism of the organism.