Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Doris A. Stoffers


LIM-domain-binding protein 1 (Ldb1) and the LIM-Homeodomain factor (LIM-HD) Islet-1 (Isl-1) share a robust functional relationship in directing differentiation of developmental progenitor populations. However, their mechanistic role in terminally differentiated cells is uncharacterized. In the developing endocrine pancreas, conditional ablation of either Isl-1 in the pancreatic epithelium or Ldb1 in the Pax6+ pancreatic endocrine progenitors suspended pancreatic endocrine differentiation. In light of their functional requirement in the developing endocrine pancreas, both factors remain ubiquitously enriched in the distinct, terminally differentiated endocrine cell-types that comprise the adult endocrine pancreas. To determine the requirement for Ldb1 and Isl-1 in the mature pancreatic β-cell, I combined physiological characterization of inducible, β-cell-specific loss-of-function mice with high-throughput cistromic and transcriptomic analyses. Ldb1 and Isl-1 were required for maintaining the glucose homeostatic role of the mature β-cell as well as the terminally differentiated status of the β-cell. Consistent with the established mechanistic relationship between Ldb1 and Isl-1 in progenitor populations, Ldb1 and Isl-1 were co-enriched throughout the β-cell genome. Comparison of our islet- and insulinoma-based cistromic data sets with the glucagonoma Isl-1 cistrome revealed differential enrichment of Isl-1 between the immortalized murine α- and β-cell lines; this differential enrichment may underlie the distinct terminal identities of α- and β-cells. Contextualized through the broader role of Ldb1-mediated complexes in directing cell fate decisions, my findings in the mature β-cell indicate that Ldb1-mediated complexes are likely responsible for directing and maintaining the terminal differentiation status of all pancreatic endocrine cell types.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."