Opto-CLIP reveals dynamic FMRP regulation of mRNAs upon CA1 neuronal activation.

Neuronal diversity and function are intricately linked to the dynamic regulation of RNA metabolism, including splicing, localization, and translation. Electrophysiologic studies of synaptic plasticity, models for learning and memory, are disrupted in Fragile X Syndrome (FXS). FXS is characterized by the loss of FMRP, an RNA-binding protein (RBP) known to bind and suppress translation of specific neuronal RNAs.

Groucho co-repressor proteins regulate β cell development and proliferation by repressing in the developing mouse pancreas.

Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of there is compensatory upregulation of double mutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and , a master regulator of the liver program.

The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function.

Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet α cell development and function has important implications for the discovery of new therapies for diabetes. In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar.

Murine Perinatal β-Cell Proliferation and the Differentiation of Human Stem Cell-Derived Insulin-Expressing Cells Require NEUROD1.

Inactivation of the β-cell transcription factor NEUROD1 causes diabetes in mice and humans. In this study, we uncovered novel functions of NEUROD1 during murine islet cell development and during the differentiation of human embryonic stem cells (HESCs) into insulin-producing cells. In mice, we determined that Neurod1 is required for perinatal proliferation of α- and β-cells.

Islet Long Noncoding RNAs: A Playbook for Discovery and Characterization.

Diabetes is a complex group of metabolic disorders that can be accompanied by several comorbidities, including increased risk of early death. Decades of diabetes research have elucidated many genetic drivers of normal islet function and dysfunction; however, a lack of suitable treatment options suggests our knowledge about the disease remains incomplete. The establishment of long noncoding RNAs (lncRNAs), once dismissed as "junk" DNA, as essential gene regulators in many biological processes has redefined the central role for RNA in cells.

Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development.

Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used a allele to ablate , one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3 endocrine progenitor lineage (). Remarkably, many essential components of the β cell transcriptional network that were down-regulated in the mice, were maintained in the mice - yet the mice displayed defective β cell differentiation and recapitulated the phenotype.

Noncoding RNAs in β cell biology.

Purpose Of Review: The identification and characterization of essential islet transcription factors have improved our understanding of β cell development, provided insights into many of the cellular dysfunctions related to diabetes, and facilitated the successful generation of β cells from alternative cell sources. Recently, noncoding RNAs have emerged as a novel set of molecules that may represent missing components of the known islet regulatory pathways. The purpose of this article is to highlight studies that have implicated noncoding RNAs as important regulators of pancreas cell development and β cell function.

A retrotransposon insertion in the 5' regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's short tail mouse.

Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2.

Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming.

Regulation of cell differentiation programs requires complex interactions between transcriptional and epigenetic networks. Elucidating the principal molecular events responsible for the establishment and maintenance of cell fate identities will provide important insights into how cell lineages are specified and maintained and will improve our ability to recapitulate cell differentiation events in vitro. In this study, we demonstrate that Nkx2.

The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration.

The homeodomain transcription factor Nkx2.2 is essential for pancreatic development and islet cell type differentiation. We have identified Tm4sf4, an L6 domain tetraspanin family member, as a transcriptional target of Nkx2.