Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets

Goto, Yutaka; Nomura, Masatoshi; Tanaka, Kimitaka; Kondo, Akiyo; Morinaga, Hidetaka; Okabe, Taijirou; Yanase, Toshihiko; Nawata, Hajime; Takayanagi, Ryoichi; Li, En

doi:10.1002/dvdy.21303

Cited by 30 publications

(22 citation statements)

References 31 publications

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“…Activin receptors (ActRII-A and ActRII-B), which may be bound by ligands in multiple TGF␤ subclasses, are expressed early in pancreatic epithelium and later in islets (Yamaoka et al 1998;Shiozaki et al 1999;Kim et al 2000;Goto et al 2007). Mice harboring null or dominant-negative mutations in these receptors as well as the downstream mediator Smad2, display decreased endocrine-hormone expression and islet hypoplasia, supporting a role for activin/TGF␤ signaling in islet development and differentiation.…”

Section: Tgf-␤ Signalingmentioning

confidence: 99%

On the origin of the β cell

Oliver‐Krasinski¹,

Stoffers²

2008

Genes Dev.

335

320

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The major forms of diabetes are characterized by pancreatic islet ␤-cell dysfunction and decreased ␤-cell numbers, raising hope for cell replacement therapy. Although human islet transplantation is a cell-based therapy under clinical investigation for the treatment of type 1 diabetes, the limited availability of human cadaveric islets for transplantation will preclude its widespread therapeutic application. The result has been an intense focus on the development of alternate sources of ␤ cells, such as through the guided differentiation of stem or precursor cell populations or the transdifferentiation of more plentiful mature cell populations. Realizing the potential for cell-based therapies, however, requires a thorough understanding of pancreas development and ␤-cell formation. Pancreas development is coordinated by a complex interplay of signaling pathways and transcription factors that determine early pancreatic specification as well as the later differentiation of exocrine and endocrine lineages. This review describes the current knowledge of these factors as they relate specifically to the emergence of endocrine ␤ cells from pancreatic endoderm. Current therapeutic efforts to generate insulin-producing ␤-like cells from embryonic stem cells have already capitalized on recent advances in our understanding of the embryonic signals and transcription factors that dictate lineage specification and will most certainly be further enhanced by a continuing emphasis on the identification of novel factors and regulatory relationships.Diabetes is rapidly becoming a global epidemic, with a staggering health, societal, and economic impact. Recent estimates by the American Diabetes Association suggest that the lifetime risk of developing diabetes for Americans born in the year 2000 is one in three. Diabetes results when insulin production by the pancreatic islet ␤ cell is unable to meet the metabolic demand of peripheral tissues such as liver, fat, and muscle.A reduction in ␤-cell function and mass leads to hyperglycemia (elevated blood sugar) in both type 1 and type 2 diabetes. In type 1 diabetes, autoimmune destruction of the ␤ cell itself severely reduces ␤-cell mass, resulting in marked hypoinsulinemia and potentially lifethreatening ketoacidosis. In contrast, during the progression to type 2 diabetes, impaired ␤-cell compensation in the setting of insulin resistance (impaired insulin action) eventually leads to ␤-cell failure and a modest but significant reduction in ␤-cell mass (Maclean and Ogilvie 1955; Butler et al. 2003;Yoon et al. 2003). More recently, autoimmunity has been detected in a subset of patients with type 2 diabetes, which has led to a revision of the classification to include LADA, latent autoimmune diabetes of adulthood, underscoring the continuum between type 1 and type 2 diabetes, and raising questions as to the role of immunity and inflammation in ␤-cell dysfunction and death in type 2 diabetes (Syed et al. 2002; Pozzilli and Buzzetti 2007). Conversely, forms of ketosis prone diabetes due to sev...

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Section: Tgf-␤ Signalingmentioning

confidence: 99%

On the origin of the β cell

Oliver‐Krasinski¹,

Stoffers²

2008

Genes Dev.

335

320

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“…Autocrine/paracrine signaling of activin, a member of the TGF-beta superfamily, through activin receptor Acvr2a is fundamentally important for ovarian follicle development (Matzuk et al 1995;Lovell et al 2007;Pangas et al 2007). In addition, the activin receptors Acvr2b and Smad2 have been shown to converge in cell signaling pathways Cold Spring Harbor Laboratory Press on May 7, 2018 -Published by genome.cshlp.org Downloaded from essential for pancreas islet formation (Goto et al 2007). We examined the mfe of mmu-let-7a-1:Acvr2a/b duplexes in the presence and absence of observed nucleotide modifications.…”

Section: Genome Research 1573mentioning

confidence: 99%

Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5′-seed/ cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes

Reid¹,

Nagaraja²,

Lynn³

et al. 2008

Genome Res.

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Massively parallel sequencing of millions of <30-nt RNAs expressed in mouse ovary, embryonic pancreas (E14.5), and insulin-secreting beta-cells (␤TC-3) reveals that ∼50% of the mature miRNAs representing mostly the mmu-let-7 family display internal insertion/deletions and substitutions when compared to precursor miRNA and the mouse genome reference sequences. Approximately, 12%-20% of species associated with mmu-let-7 populations exhibit sequence discrepancies that are dramatically reduced in nucleotides 3-7 (5Ј-seed) and 10-15 (cleavage and anchor sites). This observation is inconsistent with sequencing error and leads us to propose that the changes arise predominantly from post-transcriptional RNA-editing activity operating on miRNA:target mRNA complexes. Internal nucleotide modifications are most enriched at the ninth nucleotide position. A common ninth base edit of U-to-G results in a significant increase in stability of down-regulated let-7a targets in inhibin-deficient mice (Inha −/−). An excess of U-insertions (14.8%) over U-deletions (1.5%) and the presence of cleaved intermediates suggest that a mammalian TUTase (terminal uridylyl transferase) mediated dUTP-dependent U-insertion/U-deletion cycle may be a possible mechanism. We speculate that mRNA target site-directed editing of mmu-let-7a duplex-bulges stabilizes "loose" miRNA:mRNA target associations and functions to expand the target repertoire and/or enhance mRNA decay over translational repression. Our results also demonstrate that the systematic study of sequence variation within specific RNA classes in a given cell type from millions of sequences generated by next-generation sequencing (NGS) technologies ("intranomics") can be used broadly to infer functional constraints on specific parts of completely uncharacterized RNAs.

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“…For example, TGF␤ was previously reported to induce Smad3 phosphorylation in rat islet cells and the TGF␤ effects could be inhibited by suppressing Smad3 expression (15), although Smad2 was not investigated. On the other hand, mouse islets were hypertrophic and less functional in Smad-2 null heterozygotes (37) and Smad2 disruption in mouse ␤-cells resulted in impaired insulin secretion but islet hyperplasia probably due to compensation for hyperglycemia (38). Wu et al (13) recently reported that activin A more strongly phosphorylated pSmad2 relative to Smad3, whereas activin B preferred pSmad3 in INS-1E cells and mouse islets, with overexpression of Smad3 inhibiting insulin release, although whether these differences are functional in vivo remains controversial (14).…”

Section: Discussionmentioning

confidence: 93%

Activins A and B Regulate Fate-Determining Gene Expression in Islet Cell Lines and Islet Cells From Male Mice

et al. 2015

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TGFβ superfamily ligands, receptors, and second messengers, including activins A and B, have been identified in pancreatic islets and proposed to have important roles regulating development, proliferation, and function. We previously demonstrated that Fstl3 (an antagonist of activin activity) null mice have larger islets with β-cell hyperplasia and improved glucose tolerance and insulin sensitivity in the absence of altered β-cell proliferation. This suggested the hypothesis that increased activin signaling influences β-cell expansion by destabilizing the α-cell phenotype and promoting transdifferentiation to β-cells. We tested the first part of this hypothesis by treating α- and β-cell lines and sorted mouse islet cells with activin and related ligands. Treatment of the αTC1-6 α cell line with activins A or B suppressed critical α-cell gene expression, including Arx, glucagon, and MafB while also enhancing β-cell gene expression. In INS-1E β-cells, activin A treatment induced a significant increase in Pax4 (a fate determining β-cell gene) and insulin expression. In sorted primary islet cells, α-cell gene expression was again suppressed by activin treatment in α-cells, whereas Pax4 was enhanced in β-cells. Activin treatment in both cell lines and primary cells resulted in phosphorylated mothers against decapentaplegic-2 phosphorylation. Finally, treatment of αTC1-6 cells with activins A or B significantly inhibited proliferation. These results support the hypothesis that activin signaling destabilized the α-cell phenotype while promoting a β-cell fate. Moreover, these results support a model in which the β-cell expansion observed in Fstl3 null mice may be due, at least in part, to enhanced α- to β-cell transdifferentiation.

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Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets

Cited by 30 publications

References 31 publications

On the origin of the β cell

On the origin of the β cell

Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5′-seed/ cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes

Activins A and B Regulate Fate-Determining Gene Expression in Islet Cell Lines and Islet Cells From Male Mice

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