Primary cilia in pancreatic development and disease

Lodh, Sukanya; O’Hare, Elizabeth A.; Zaghloul, Norann A.

doi:10.1002/bdrc.21063

Cited by 41 publications

(41 citation statements)

References 247 publications

(342 reference statements)

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“…Pancreatic, biliary and renal development is known to be dependent on normal ciliary function. Loss of function or mutation of some proteins in the ciliary membrane or of proteins involved in cilium building lead to renal, biliary and pancreatic cystogenesis in human and mouse [34, 35, 36]. As noted previously, mice lacking AC3 have no reported kidney, pancreas or liver malformation, in accordance with our results.…”

Section: Discussionsupporting

confidence: 92%

Adenylate Cyclase Type III Is Not a Ubiquitous Marker for All Primary Cilia during Development

et al. 2017

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Adenylate cyclase type III (AC3) is localized in plasma membrane of neuronal primary cilium and can be used as a marker of this cilium. AC3 has also been detected in some other primary cilia such as those of fibroblasts, synoviocytes or astrocytes. Despite the presence of a cilium in almost all cell types, we show that AC3 is not a common marker of all primary cilia of different human and mouse tissues during development. In peripheral organs, AC3 is present mainly in primary cilia in cells of the mesenchymal lineage (fibroblasts, chondroblasts, osteoblasts-osteocytes, odontoblasts, muscle cells and endothelial cells). In epithelia, the apical cilium of renal and pancreatic tubules and of ductal plate in liver is AC3-negative whereas the cilium of basal cells of stratified epithelia is AC3-positive. Using fibroblasts cell culture, we show that AC3 appears at the plasma membrane of the primary cilium as soon as this organelle develops. The functional significance of AC3 localization at the cilium membrane in some cells but not others has to be investigated in relationship with cell physiology and expression at the cilium plasma membrane of specific upstream receptors.

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Section: Discussionsupporting

confidence: 92%

Adenylate Cyclase Type III Is Not a Ubiquitous Marker for All Primary Cilia during Development

et al. 2017

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“…Primary cilia are present on the majority of vertebrate cell types and act as cellular hubs for sensing and transducing signaling pathways (1). Deletions in ciliary genes—including basal body proteins, transition zone components, and intraflagellar transport elements—are implicated in a class of diseases termed the ciliopathies which exhibit a broad range of phenotypes (2,3). A unique subset among these disorders are the obesity ciliopathies that present with highly penetrant, early onset obesity.…”

Section: Introductionmentioning

confidence: 99%

Genomic knockout ofalms1in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

Nesmith

Hostelley

Leitch

et al. 2018

Preprint

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SCIENTIFIC ABSTRACTAlström syndrome is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration, and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early onset type 2 diabetes mellitus (T2DM). To investigate mechanisms linking disease phenotypes we generated a loss-of-function deletion of alms1 in the zebrafish using CRISPR/Cas9. We demonstrate conserved phenotypic effects including cardiac defects, retinal degeneration, and metabolic deficits that included propensity for obesity and fatty livers in addition to hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1−/− mutants revealed changes consistent with insulin hyper-secretion and glucose sensing failure, which were also identified in cultured murine β-cells lacking Alms1. These data present a zebrafish model to assess etiology and new secretory pathway defects underlying Alström syndrome-associated metabolic phenotypes. Given the hyperinsulinemia and reduced glucose sensitivity in these animals we also propose the alms1 loss-of-function mutant as a monogenic model for studying T2DM phenotypes.AUTHOR SUMMARYThese data comprise a thorough characterization of a zebrafish model of Alström syndrome, a human obesity syndrome caused by loss-of-function deletions in a single gene, ALMS1. The high rates of obesity and insulin resistance found in these patients suggest this disorder as a single-gene model for Type 2 Diabetes Mellitus (T2DM), a disorder caused by a variety of environmental and genetic factors in the general population. We identify a propensity for obesity, excess lipid storage, loss of β-cells in islets, and hyperinsulinemia in larval and adult stages of zebrafish alms1 mutants. We isolated β-cells from the alms1 mutants and compared the gene expression profiles from RNASeq datasets to identify molecular pathways that may contribute to the loss of β-cells and hyperinsulinemia. The increase in genes implicated in generalized pancreatic secretion, insulin secretion, and glucose transport suggest potential β-cell exhaustion as a source of β-cell loss and excess larval insulin. We propose this mutant as a new genetic tool for understanding the metabolic failures found in Type 2 Diabetes Mellitus.

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“…Neurog3 is central in this process as this gene is essential for endocrine cell fate determination and the initiation of islet differentiation programs resulting into the the different pancreatic endocrine cell types including insulin-secreting β-cells (Desgraz and Herrera 2009; Gradwohl, et al 2000; Gu, et al 2002). While a series of growth factors controlling early steps of pancreas organogenesis have been identified (see for a review (Lodh, et al 2014; Mastracci and Sussel 2012)) we currently lack information on the nature of signals that would eventually control later steps of islet differentiation including endocrine cell fate decision, survival of endocrine progenitors, islet subtype specification, and maturation. As such a knowledge could be instrumental to improve the generation of glucose responsive β-cells in vitro we searched for endocrine progenitors cell surface receptors.…”

Section: Introductionmentioning

confidence: 99%

Expression and functional studies of the GDNF family receptor alpha 3 in the pancreas

Nivlet

Herrmann

Martin

et al. 2015

Journal of Molecular Endocrinology

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The generation of therapeutic β-cells from human pluripotent stem cells relies on the identification of growth factors that faithfully mimic pancreatic β-cell development in vitro. In this context, the aim of the study was to determine the expression and function of the Glial cell line derived neurotrophic factor receptor α 3 (GFRα3) and its ligand Artemin in islet cell development and function. GFRα3 and Artn expression were characterized by in situ hybridization, immunochemistry and qRT-PCR. We used GFRα3-deficient mice to study GFRα3 function and generated a transgenic mice overexpressing Artn in the embryonic pancreas to study Artn function. We found that GFRα3 is expressed at the surface of a subset of Ngn3-positive endocrine progenitors as well as of embryonic α- and β-cells, while Artn is found in the pancreatic mesenchyme. Adult β-cells lack GFRα3 but α-cells express the receptor. GFRα3 was also found in parasympathetic and sympathetic intra islets neurons as well as in glial cells in the embryonic and adult pancreas. The loss of GFRα3 or overexpression of Artn has no impact on Ngn3- and islet- cells formation and maintenance in the embryo. Islet organisation and innervation as well as glucose homeostasis is normal in GFRα3-deficient mice suggesting functional redundancy.

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Primary cilia in pancreatic development and disease

Cited by 41 publications

References 247 publications

Adenylate Cyclase Type III Is Not a Ubiquitous Marker for All Primary Cilia during Development

Adenylate Cyclase Type III Is Not a Ubiquitous Marker for All Primary Cilia during Development

Genomic knockout ofalms1in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

Expression and functional studies of the GDNF family receptor alpha 3 in the pancreas

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