Stimulation of Activin Receptor II Signaling Pathways Inhibits Differentiation of Multiple Gastric Epithelial Lineages

Li, Qiutang; Karam, Sherif M.; Coerver, Katherine A.; Matzuk, Martin M.; Gordon, Jeffrey I.

doi:10.1210/mend.12.2.0060

Cited by 53 publications

(21 citation statements)

References 34 publications

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“…In addition, mice deficient in the type II activin receptors (ActRIIA ϩ/-Act RIIB -/-embryos) have disrupted development of the glandular stomach and over-expression of Shh in the distal stomach (Kim et al, 2000). Gastric epithelial cell differentiation also has been shown to be disrupted by persistent stimulation of Type II activin receptors (Matzuk et al, 1995;Li et al, 1998). These observations, coupled with the results of the present study, suggest that GATA-4:FOG-1 interactions play a role in mediating TGF-␤ signaling in gastric endoderm.…”

Section: Discussionsupporting

confidence: 77%

GATA‐4:FOG interactions regulate gastric epithelial development in the mouse

Jacobsen¹,

Mannisto²,

Porter-Tinge³

et al. 2005

Developmental Dynamics

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Transcription factor GATA-4 is a key participant in cytodifferentiation of the mouse hindstomach. Here we show that GATA-4 cooperates with a Friend-of-GATA (FOG) cofactor to direct gene expression in this segment of gut. Immunohistochemical staining revealed that GATA-4 and FOG-1 are co-expressed in hindstomach epithelial cells from embryonic days (E) 11.5 to 18.5. The other member of the mammalian FOG family, FOG-2, was not detected in gastric epithelium. To show that GATA-4:FOG interactions influence stomach development, we analyzed Gata4 ki/ki mice, which express a mutant GATA-4 that cannot bind FOG cofactors. Sonic Hedgehog, an endoderm-derived signaling molecule normally down-regulated in the distal stomach, was over-expressed in hindstomach epithelium of E11.5 Gata4 ki/ki mice, and there was a concomitant decrease in fibroblast growth factor-10 in adjacent mesenchyme. We conclude that functional interaction between GATA-4 and a member of the FOG family, presumably FOG-1, is required for proper epithelial-mesenchymal signaling in the developing stomach. Developmental Dynamics 234:355-362, 2005.

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Section: Discussionsupporting

confidence: 77%

GATA‐4:FOG interactions regulate gastric epithelial development in the mouse

Jacobsen¹,

Mannisto²,

Porter-Tinge³

et al. 2005

Developmental Dynamics

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“…In mice deficient of the inhibin α gene, sex cord-stromal tumors developed as early as 4 weeks of age both in males and females [57]. The tumors cause an activindependent cachexia and wasting syndrome and affects mordality due to the absence of inhibin [58]. Activins secreted from tumors activate ACVR2 in excess and cause apoptosis of hepatocytes [57].…”

Section: Cancersmentioning

confidence: 99%

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

et al. 2008

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Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.

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“…23 The signals mediating gland cell migration and differentiation in the distal stomach are only partially understood, but the transition from mucopeptic cells to chief cells requires the activity of transcription factor Mist1 24 and can be inhibited by stimulation of activin II receptor. 25 The development and persistence of pepsinogen-expressing cells, and particularly chief cells, require glucocorticoids, 26,27 whose homeostatic effects are mediated via the mesenchymal stroma. 28 This stroma, the lamina propria, consisting of fibroblasts, endothelial, and immune cells, is located between and underneath the gastric units.…”

mentioning

confidence: 99%

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Udd

Katajisto

Kyyrönen

et al. 2010

The American Journal of Pathology

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Gastrointestinal hamartomatous polyps in the PeutzJeghers cancer predisposition syndrome and its mouse model (Lkb1؉/؊ ) are presumed to contain all cell types native to the site of their occurrence. This study aimed to explore the pathogenesis of PeutzJeghers syndrome polyposis by characterizing cell types and differentiation of the epithelium of gastric polyps and predisposed mucosa. Both antral and fundic polyps were characterized by a deficit of pepsinogen C-expressing differentiated gland cells (antral gland, mucopeptic, and chief cells); in large fundic polyps, parietal cells were also absent. Gland cell loss was associated with an increase in precursor neck cells, an expansion of the proliferative zone, and an increase in smooth muscle ␣-actin expressing myofibroblasts in the polyp stroma. Lack of pepsinogen C-positive gland cells identified incipient polyps, and even the unaffected mucosa of young predisposed mice displayed an increase in pepsinogen C negative glands (25%; P ‫؍‬ 0045). In addition, in small intestinal polyps, gland cell differentiation was defective, with the absence of Paneth cells. There were no signs of metaplastic differentiation in any of the tissues studied, and both the gastric and small intestinal defects were seen in Lkb1 ؉/؊ mice, as well as polyps from patients with Peutz-Jeghers syndrome. These results identify impaired epithelial differentiation as the earliest pathological sign likely to contribute to tumorigenesis in individuals with inherited Lkb1 mutations. (Am J

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Stimulation of Activin Receptor II Signaling Pathways Inhibits Differentiation of Multiple Gastric Epithelial Lineages

Cited by 53 publications

References 34 publications

GATA‐4:FOG interactions regulate gastric epithelial development in the mouse

GATA‐4:FOG interactions regulate gastric epithelial development in the mouse

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

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