Deciphering the Role of Eukaryotic Initiation Factor 5A in Pancreatic Organogenesis

Abstract

The pancreas is composed of a variety of cell types such as acinar, endocrine, and ductal cells, as well as endothelial cells and adipocytes. Whereas we understand the distinct functions of each, there remains an incomplete understanding of the molecular pathways and communications that exist between these cells that may influence development, growth, and function. Given that diabetes is characterized by the destruction or dysfunction of the insulin-producing pancreatic beta cell, a better understanding of the mechanisms that influence cell growth and maintenance in the pancreas is of therapeutic interest. Genome-wide association studies identified eukaryotic initiation factor 5A (eIF5A) to be within a type 1 diabetes susceptibility locus, which also suggests this translation factor may play a role in maintaining beta cell health. EIF5A is active once post-translationally modified by the rate-limiting enzyme deoxyhypusine synthase (DHPS) in a process known as hypusination, producing hypusinated eIF5A (eIF5AHYP). The functional loss of eIF5AHYP via pancreas-specific genetic deletion of Dhps or Eif5a within multipotent pancreatic progenitor cells (MPPCs) results in an mRNA translation defect detectable at E14.5 causing the decreased expression of many proteins required for exocrine growth and function. Moreover, DHPSΔPANC mice die by 6 weeks-of-age; however, eIF5AΔPANC mice survive up to 2 years-of-age. The postnatal phenotype of the eIF5AΔPANC model was investigated in this thesis.