MicroRNA-7 regulates endocrine progenitor delamination and endocrine cell mass in developing pancreatic islets.

β-cell replenishment in patients with diabetes through cadaveric islet transplantation has been successful; however, it requires long-term immunosuppression and suitable islet donors are scarce. Stepwise differentiation of pluripotent stem cells into β-cells represents a viable alternative, but limitations in our current understanding of islet endocrine differentiation constrains its clinical use. Here, we show that microRNA-7 (miR-7) is highly expressed in embryonic pancreatic endocrine progenitors.

Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease.

Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy.

Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes.

Objective: β-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. We previously showed that increased miR-7 levels trigger β-cell dedifferentiation and diabetes. We used β-cell-specific miR-7 overexpressing mice (Tg7) to test the hypothesis that loss of β-cell identity triggered by miR-7 overexpression alters islet gene expression and islet microenvironment in diabetes.

Neuronatin regulates pancreatic β cell insulin content and secretion.

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone- and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess.

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility.

MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood.

MiRNAs in β-Cell Development, Identity, and Disease.

Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell "identity" and dedifferentiation also contribute to the decline in insulin production.

miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development.

Unlabelled: MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown.

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes.

Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D.

MicroRNA-7a regulates pancreatic β cell function.

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells.

Interaction of Nck1 and PERK phosphorylated at Y⁵⁶¹ negatively modulates PERK activity and PERK regulation of pancreatic β-cell proinsulin content.

PERK, the PKR-like endoplasmic reticulum (ER) kinase, is an ER transmembrane serine/threonine protein kinase activated during ER stress. In this study, we provide evidence that the Src-homology domain-containing adaptor Nck1 negatively regulates PERK. We show that Nck directly binds to phosphorylated Y(561) in the PERK juxtamembrane domain through its SH2 domain.

Casein kinase iγ2 impairs fibroblasts actin stress fibers formation and delays cell cycle progression in g1.

Actin cytoskeleton remodeling is under the regulation of multiple proteins with various activities. Here, we demonstrate that the γ2 isoform of Casein Kinase I (CKIγ2) is part of a novel molecular path regulating the formation of actin stress fibers. We show that overexpression of CKIγ2 in fibroblasts alters cell morphology by impairing actin stress fibers formation.

Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice.

Obesity has been shown to create stress in the endoplasmic reticulum (ER), and that initiates the activation of the unfolded protein response (UPR). This has been reported to cause insulin resistance in selective tissues through activation of the inositol-requiring enzyme 1α (IRE1α)-c-Jun NH(2)-terminal kinase (JNK) pathway, which results in the phosphorylation of the insulin receptor substrate-1 (IRS-1) at an inhibitory site and blocks insulin receptor signaling. In this study, we report that the Src homology domain-containing adaptor protein Nck1, previously shown to modulate the UPR, is of functional importance in obesity-induced ER stress signaling and inhibition of insulin actions.

Nck-1 selectively modulates eIF2alphaSer51 phosphorylation by a subset of eIF2alpha-kinases.

Phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2) on Ser51 is an early event associated with the down-regulation of protein synthesis at the level of translation and initiation of a transcriptional program. This constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2alpha-kinases [PKR-like endoplasmic reticulum kinase (PERK), dsRNA-activated protein kinase (PKR), heme regulated inhibitor (HRI) and general control nonderepressible-2 (GCN2)], activated following specific stresses, have been shown to be involved in this process.

Rat nephrin modulates cell morphology via the adaptor protein Nck.

Nephrin is a transmembrane molecule essential for morphology and function of kidney podocytes. We and others reported previously that the cytoplasmic domain of human and mouse nephrin interacts with the adaptor protein, Nck, in a tyrosine phosphorylation-dependent manner. In the current study, we characterized the interaction of rat nephrin with Nck and further addressed its impact on cell morphology.

Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress.

Stress imposed on the endoplasmic reticulum (ER) induces the phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2) on Ser51. This results in transient inhibition of general translation initiation while concomitantly activating a signaling pathway that promotes the expression of genes whose products improve ER function. Conversely, dephosphorylation of eIF2alphaSer51 is accomplished by protein phosphatase 1 (PP1c) complexes containing either the protein CReP or GADD34, which target PP1c to eIF2.

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse.

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell.