Diabetes Caused by Elastase-Cre-Mediated Pdx1 Inactivation in Mice.

Masashi Horiguchi,Koji Hirata,Shinji Uemoto,Michiya Kawaguchi,Christopher V E Wright,Kenichiro Furuyama,Takeshi Kuhara,Yoshiya Kawaguchi,Yasuhiro Nakano,Sota Kodama,Toshihiko Masui,Maureen Gannon

doi:10.1038/srep21211

Masashi Horiguchi, Koji Hirata + Show 10 more

Open Access

https://doi.org/10.1038/srep21211

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Journal: Scientific reports	Publication Date: Feb 18, 2016
Citations: 16	License type: CC BY 4.0

Affiliation: Kyoto University, Vanderbilt University

Abstract

Endocrine and exocrine pancreas tissues are both derived from the posterior foregut endoderm, however, the interdependence of these two cell types during their formation is not well understood. In this study, we generated mutant mice, in which the exocrine tissue is hypoplastic, in order to reveal a possible requirement for exocrine pancreas tissue in endocrine development and/or function. Since previous studies showed an indispensable role for Pdx1 in pancreas organogenesis, we used Elastase-Cre-mediated recombination to inactivate Pdx1 in the pancreatic exocrine lineage during embryonic stages. Along with exocrine defects, including impaired acinar cell maturation, the mutant mice exhibited substantial endocrine defects, including disturbed tip/trunk patterning of the developing ductal structure, a reduced number of Ngn3-expressing endocrine precursors, and ultimately fewer β cells. Notably, postnatal expansion of the endocrine cell content was extremely poor, and the mutant mice exhibited impaired glucose homeostasis. These findings suggest the existence of an unknown but essential factor(s) in the adjacent exocrine tissue that regulates proper formation of endocrine precursors and the expansion and function of endocrine tissues during embryonic and postnatal stages.

Highlights

The mature pancreas is composed of two functional components: exocrine and endocrine tissue
Pancreatic and duodenal homeobox[1] (Pdx1), which is the causative gene of maturity-onset diabetes of the young 4 (MODY4)[7,8], regulates the transcription of genes involved in glucose homeostasis, such as insulin, glucokinase and glucose transporter type 2 (GLUT2), in adult β cells[9,10,11]
We demonstrate that the mutant mice showed exocrine defects, and fewer endocrine precursors and endocrine cells with less proliferation and delayed maturation, resulting in impaired glucose homeostasis

Summary

Introduction

The mature pancreas is composed of two functional components: exocrine and endocrine tissue. In hypomorphic Ptf1a mutants, the timing of endocrine cell differentiation was normal, but the total number of insulin-producing β cells was substantially reduced and the structure of islets disturbed, resulting in impaired glucose homeostasis These findings supported the hypothesis that exocrine pancreatic tissue functions as a matrix necessary for proper endocrine pancreas formation[4]. We demonstrate that the mutant mice showed exocrine defects, and fewer endocrine precursors and endocrine cells with less proliferation and delayed maturation, resulting in impaired glucose homeostasis These findings support the notion that the exocrine pancreas is required for proper endocrine development and function, and that normal development of the pancreas occurs in an interactive, coordinated manner between the two tissues

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