All ETDs from UAB

Advisory Committee Chair

David Schneider

Advisory Committee Members

Ron Banerjee

Chenbei Chang

Chad Hunter

Hubert Tse

Document Type

Thesis

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The prevalence and tremendous impact of diabetes mellitus has made glucose regulation of the insulin-producing -cell and surrounding pancreatic islet of Langerhans a center of public and research interests alike. A comprehensive understanding of these hormone-producing cells begins with their developmental origins. What are the genetic cues and participants in the tightly orchestrated process of their formation? Investigating the earliest determinants of islet-cell fate not only allows us to deeply understand mature - and islet-cell function, but also produces a data-driven template for how these cells can be reproduced in future stem-cell based diabetes therapies. LIM transcriptional complexes are indispensable drivers of early developmental cell-fate across tissues and species and the objective of this dissertation was to explore the roles of two LIM complex coregulators, Ldb1 and SSBP3, in pancreatic progenitor development, specification, and mature function. In the experiments outlined in Chapter 2, I generate two novel Ldb1- deficient mouse models, one in the developing pancreas and another specifically in pancreatic endocrine progenitors. Striking blood glucose defects upon birth and nearcomplete loss of islet cells established Ldb1 as a key determinant of pancreatic endocrine cell identity. Defects in early fate choice of pancreatic progenitors highlighted that Ldb1 plays a role in directing progenitors towards islet-cell fate. Ldb1 occupied known regulatory regions of key developmental genes Pdx1 and Ngn3, illustrating direct regulation by a LIM-complex. In Chapter 3, I characterize SSBP3, another critical iv component of LIM-complex regulation that had been unexplored in the pancreas in vivo. Using a novel SSBP3 floxed mouse designed by our lab and developmental and adultinducible deletion strategies, I generate three novel mouse models that reveal SSBP3 to be required for proper islet-cell abundance, architecture, and adult -cell identity and function. The work presented here demonstrates essential roles for Ldb1 and SSBP3 as essential determinants of islet and -cell fate and function. Ldb1 and SSB3 regulation of pancreatic endocrine cell identity provides novel insights into the members of the transcriptional “LIM code” driving identity of diverse cell populations in the pancreas

Share

COinS