The Ldb1 transcriptional co‐regulator is required for establishment and maintenance of the pancreatic endocrine lineage

Abstract

Pancreatic islet cell development is regulated by transcription factors (TFs) that mediate embryonic progenitor differentiation toward mature endocrine cells. Prior studies from our lab and others showed that the islet‐enriched TF, Islet‐1 (Isl1), interacts with the broadly‐expressed transcriptional co‐regulator, Ldb1, to regulate islet cell maturation and postnhyperatal function (by embryonic day (E)18.5). However, Ldb1 is expressed in the developing pancreas prior to Isl1 expression, notably in multipotent progenitor cells (MPCs) marked by Pdx1 and endocrine progenitors (EPs) expressing Neurogenin‐3 (Ngn3). MPCs give rise to the endocrine and exocrine pancreas, while Ngn3+ EPs specify pancreatic islet endocrine cells. We hypothesized that Ldb1 is required for progenitor identity in MPC and EP populations during development to impact islet appearance and function. To test this, we generated a whole‐pancreas Ldb1 knockout, termed Ldb1ΔPanc, and observed severe developmental and postnatal pancreas defects including disorganized progenitor pools, a significant reduction of Ngn3‐expressing EPs, Pdx1HI β‐cells, and early hormone+ cells. Ldb1ΔPanc neonates presented with severe hyperglycemia, hypoinsulinemia, and drastically reduced hormone expression in islets, yet no change in total pancreas mass. This supports the endocrine‐specific actions of Ldb1. Considering this, we also developed an endocrine‐enriched model of Ldb1 loss, termed Ldb1ΔEndo. We observed similar dysglycemia in this model, as well as a loss of islet identity markers. Through in vitro and in vivo chromatin immunoprecipitation experiments, we found that Ldb1 occupies key Pdx1 and Ngn3 promoter domains. Our findings provide insight into novel regulation of endocrine cell differentiation that may be vital toward improving cell‐based diabetes therapies.

The SSBP3 co-regulator is required for glucose homeostasis, pancreatic islet architecture, and beta-cell identity

“…At P1, pancreata were collected, weighed for pancreatic mass index calculation (pancreas weight/total body weight × 100 [ 20 ]), and formaldehyde fixed for histology. Trunk blood was collected from P1 and P10 mice and blood glucose measured using an automatic glucometer (Bayer Contour Next).…”

“…The widely-expressed transcriptional co-regulator LIM-domain binding protein-1 (Ldb1) interacts with LIM-HD TFs, including Isl1, to impact transcription of diverse genes during development [ 18 ]. In the pancreas, our lab and others have shown that robust Ldb1::Isl1 interactions are required for islet-cell identity and function both during development and in the adult β-cell [ 16 , 19 , 20 ]. Ldb1 contains a dimerization (DD) and LIM-interaction domain (LID) allowing it to act as a dimerized scaffold for stabilizing large transcriptional complexes.…”