Revealing LIM-Domain Transcriptional Complexes that Establish and Maintain Alpha-Cell Mass

University Of Kansas Medical Center, Kansas City KS

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Abstract

PROJECT SUMMARY/ABSTRACT Pancreatic islets of Langerhans contain insulin-secreting β-cells and glucagon-producing α-cells that function in concert to maintain glucose homeostasis. Dysfunction in islet activity, cell identity, or survival results in diabetes mellitus, a disease affecting millions of Americans with numbers expected to greatly increase. It is known that dysregulated α-cells are also major contributors to type 1 and type 2 diabetes, yet the research focus for decades has largely been on the β-cell. Thus, the key regulators driving α-cell development and adult function are much less defined than in β-cells. Increased knowledge of the effectors of embryonic α-cell development will be instructive for generating ES cell-derived α-cells for islet replacement therapies, while a greater understanding of adult α-cell functional identity will help us understand how the α-cell responds to glucose dysregulation, likely providing novel therapeutic strategies. We and others previously demonstrated that the Islet-1 transcription factor is required for mouse β-cell development and function and has human gene variants that are strongly linked to islet function and diabetes. In addition, transcriptional control imposed by Islet-1 in β-cells requires the interacting co-regulator, LDB1, with strong evidence for Islet-1:LDB1 complex activity also in α-cells. However, nothing is known of the mouse or human α-cell target genes and pathways governed by these factors. Interestingly, the complexity of LDB1- mediated transcriptional control is also greater than simply through Islet-1, potentially involving other islet- enriched transcription factors including GATA6 and/or NEUROD1. These observations support that LDB1 may mediate multiple distinct α-cell complexes to elicit transcriptional and functional impacts. Three complementary Aims will define comparative roles of Islet-1 and LDB1 during embryonic mouse development and adult mouse and human α-cell function. Preliminary embryonic knockout model data suggests that α-cell Islet-1 and LDB1 are each required to maintain postnatal glucose homeostasis. We will further explore the impacts of α-cell-specific Islet-1 or LDB1 deficiency in developing and postnatal mice, and in donor human islets. This proposal will test the hypothesis that Ldb1-mediated complexes comprise a central node to regulate transcription in multiple phases of mammalian α-cell development and postnatal function, through Islet-1 and potentially other islet transcription factors. Our extensive experience studying transcription factor complexes and readily-available in vitro and in vivo reagents, make us uniquely suited for executing these Aims. Results reported from this proposal will benefit efforts in developing new molecular targets and cell-based therapies to combat diabetes.