The islets of Langerhans are organoids within the pancreas that are high functioning, tightly regulated machines with specific hormones secreted from various endocrine cell-types, which intercommunicate with each other and the sympathetic and parasympathetic neural network. Contact with the capillary bed allows rapid response to glucose or other regulators from the bloodstream. The major endocrine types in the mature islet are alpha (α; secreting glucagon), beta (β; insulin), delta (δ; somatostatin), and PP (pancreatic polypeptide). The β cells are most important because of the central role of insulin (Ins) in glycemic control. Islet endocrine cells communicate with themselves. The β cells use gap-junction coupling for efficient glucose-stimulated insulin secretion (GSIS). Glucagon (Gcg) is involved in the counter-regulatory response to glucose, and somatostatin (Som) is an essential limiting influence on β cells, preventing insulin over-secretion and hypoglycemia. This minimizes the exhaustion of b cells under a repeated-release stimulus and allows a lifetime of normal function. Normal β cells are very quiescent with respect to mitosis, and under β-cell stress or failure (loss of phenotype, death), their minimal replicative capacity cannot keep up with the body's physiological needs. Our recently published conditional inactivation of the β-cell-specific transcription factor (TF) gene Mnx1 (Pan et al., Development 2016) provides new ways of dissecting the mechanisms allocating endocrine progenitors to the β-cell lineage, and maintaining fate by blocking transdifferentiation to Som+ δ-like cells. In a context wherein most β cells undergo Mnx1-inactivation and transdifferentiation to Som+ cells, a few “escaper” β cells remain Mnx1+. In the presence of a great number of nearby Som+Hhex+ transdifferentiated β cells, these escapers enter a hyperproliferative state that seems to persist over the entire life of the animal, leading to hyperplastic islets filled with apparently normal, mature β cells. We address the role of Mnx1 in controlling early β-cell lineage allocation and later-stage maintenance of β-cell fate and function. We will determine if the signal inducing β-cell proliferation is derived from the transdifferentiated δ or δ-like cells, if it works islet-locally, if it requires synergy with other signals, and if it can work similarly on very old β cells. We will examine Mnx1 expression and depletion effects in human β cells, β-like cell lines, and normal tissue samples. We will clarify the various sets of Mnx1 target genes and epigenetic guidance effects in maturing and older β cells. We test our novel hypothesis that there are “lineage/fate consolidation checkpoints” at which gene regulatory networks (GRNs) begin further optimization (augmentation/pruning) in normal tissue, or at which cryptically deficient GRNs undergo reconfiguration to lead to explicit lineage/fate conversion. Our generation of a more rigorous understanding of δ and conve...