The role of TGF‐βs in mammalian development and neoplasia

Akhurst, Rosemary J.; FitzPatrick, David R.; Fowlis, Deborah; Gatherer, Derek; Millan, Fergus A.; Slager, H.G.

doi:10.1002/mrd.1080320208

Cited by 27 publications

(18 citation statements)

References 22 publications

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“…The pattern of distribution of AM-like immunoreactivity and its mRNA during murine development is very similar to that of other well established peptide growth factors. The distribution of AM immunoreactivity shown in our study is very similar to that reported for the TGF␤ isoforms 1, 2, and 3 in the E12-18.5 mouse embryos (2,27), suggesting that AM and the TGF␤s could be involved in analogous functions. AM distribution also shows some coincident locations with other active peptides such as PDGF, the fibroblast growth factors, insulin-like growth factors I and II, and the recently discovered cardiotropin, a member of the leukemia inhibitory factor/interleukin-6 family.…”

Section: Discussionsupporting

confidence: 88%

Expression of Adrenomedullin and Its Receptor during Embryogenesis Suggests Autocrine or Paracrine Modes of Action

et al. 1997

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The present study reports the developmental patterns of expression of adrenomedullin (AM) in rat and mouse embryos. AM is a novel multifunctional peptide recently isolated from a human pheochromocytoma, which has been shown to promote growth in a variety of mammalian cell lines. We have applied several techniques to investigate the localization of both the AM peptide and its receptor throughout development. Immunocytochemical detection has been performed using different specific antibodies against AM and its generelated peptide pro-AM N-terminal 20 peptide. In situ hybridization showed the localization of the messenger RNAs for AM and its receptor. Western blot analysis together with reverse transcription-PCR gave further support to the localization of AM and its receptor in a variety of embryonic tissues. The localization of the receptor paralleled that of AM itself, suggesting an autocrine or paracrine mode of action. The spatio-temporal pattern of expression of AM in cardiovascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs is described. The primitive placenta, especially the giant trophoblastic cells, shows high levels of AM and AM receptor. The heart is the first organ that expresses AM during development. The kidney, lung, and developing tooth, in which epithelial-mesenchymal interactions are taking place, show specific patterns of AM expression. In several regions of the embryo, the patterns of AM expression correspond to the degree of differentiation. The possible involvement of AM in the control of embryonic invasion, proliferation, and differentiation is discussed. (Endocrinology 138: 440 -451, 1997) A DRENOMEDULLIN (AM) is a multifunctional peptide that has been identified from extracts of human pheochromocytoma (18). It is comprised of 52 amino acids and shows slight structural homology with calcitonin gene-related peptide (CGRP). Initial characterization demonstrated AM as a potent mediator of hypotension when injected iv into rats (18). AM and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), are the two known bioactive amidated peptides generated by posttranslational enzymatic processing of the 185-amino acid prepro-AM molecule (19). AM elevates intracellular cAMP levels in several cell types, and a receptor for AM (AM-R) has recently been cloned and sequenced (16). PAMP has no sequence homology with AM or CGRP and seems to act via a different receptor system (30). The expression of AM has been shown in a variety of adult rat, human, and porcine tissues, including heart, adrenals, brain, kidney, pancreas, aorta, lung, and brain-and lung-derived tumors (10,23,24,31).Apart from the vasorelaxant effect, several other functions have been reported for this peptide hormone. AM has been implicated in the regulation of renal function by means of its potent natriuretic and diuretic properties (14), has bronchodilatory effects (15), and inhibits the release of aldosterone, ACTH, and insulin (24,28). Recent data suggest the involv...

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Section: Discussionsupporting

confidence: 88%

Expression of Adrenomedullin and Its Receptor during Embryogenesis Suggests Autocrine or Paracrine Modes of Action

et al. 1997

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“…The embryonic heart will start to pulsate at day 8.5-9 pc [Rugh, 19681, so that the formation of beating muscle in aggregates follows similar kinetics. We have obtained evidence that both TGF-p2 protein and mRNA are present in the embryonic heart and associated regions at day 8-8.5 pc [Akhurst et al, 1992;Dickson et al, 19931. Cardiac myocytes but not endocardium or cushion cells stain intensively with a polyclonal antibody specific for TGF-fi2.…”

Section: Discussion Embryonic Stem Cells and Tgf-pmentioning

confidence: 96%

Transforming growth factor‐β in the early mouse embryo: Implications for the regulation of muscle formation and implantation

et al. 1993

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In a search for functions of transforming growth factor-beta during early embryonic development we used two different experimental approaches. In the first we made use of embryonic stem (ES) cells. ES cells in culture differentiate to derivatives of all three germ layers and mimic some aspects of organogenesis when grown as aggregates in suspension to form embryoid bodies. Differentiation proceeds further when the embryoid bodies attach to suitable substrates. Muscle and neuronal cells are among the most readily identified cell types then formed. We examined the effect of all-trans retinoic acid (RA) and members of the transforming growth factor-beta family (TGF-beta 1, TGF-beta 2) under these conditions in an assay where single aggregates formed in hanging microdrops in medium supplemented with serum depleted of lipophilic substances which would include retinoids. Endoderm-like cells formed under all conditions tested. RA at concentrations of 10(-8) M and 10(-7) M induced the formation of neurons but in the absence of RA or at concentrations up to 10(-9) M, neurons were not observed. Instead, beating muscle formed in about one-third of the plated aggregates; this was greatly reduced when RA concentrations increased above 10(-9) M. Immunofluorescent staining for muscle specific myosin showed that two muscle cell types could be distinguished: elongated, non-contractile myoblasts and mononucleate flat cells. The mononucleate flat cells appeared to correspond with rhythmically contracting muscle. The number of non-contractile myoblasts increased 3-fold over controls in the presence of 10(-9) M RA. TGF-beta s increased the number of contractile and non-contractile muscle cells by a factor 3 to 7 over controls, depending on the TGF-beta isoform added and the muscle cell type formed. TGF-beta 2 also invariably increased the rate at which contracting muscle cells were first observed in replated aggregates. The stimulatory effect of TGF-beta s on the formation of mononucleate flat cells was completely abrogated by RA at 10(-9) M while the number of myoblasts under similar conditions was unchanged. These data suggest that a complex interplay between retinoids and TGF-beta isoforms may be involved in regulation of differentiation in early myogenesis. In the second approach, neutralizing polyclonal rabbit antibodies specific for TGF-beta 2 were injected into the cavity of mouse blastocysts 3.5 days post coîtum (pc). After 1 day in culture, embryos were transferred to pseudopregnant females. The number of decidua, embryos and resorptions were counted at day 8.5-9.5 pc.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…conservation of function between these two organisms (Akhurst et al, 1992;Gatherer et al, 1990). Moreover, the finding of vascular dysplasia and malformation resulting from germ-line loss of TGF␤ signaling components in the hereditary hemorrhagic telangiectasias (HHTs) (Berg et al, 1997;McAllister et al, 1994), familial thoracic aortic aneurysms and dissections (FTAAD) (Pannu et al, 2005) and other cardiovascular malformations (Loeys et al, 2005;Mizuguchi et al, 2004), emphasizes the importance of TGF␤ signaling in vascular remodeling and homeostasis in humans (Akhurst, 2004).…”

Section: Introductionmentioning

confidence: 99%

TGFβ inhibition of yolk-sac-like differentiation of human embryonic stem-cell-derived embryoid bodies illustrates differences between early mouse and human development

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Clermont

Firpo

et al. 2006

Journal of Cell Science

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Transforming growth factor β (TGFβ) plays an important role in development and maintenance of murine yolk sac vascular development. Targeted deletions of Tgfb1 and other components of this signaling pathway, such as Acvrl1, Tgfbr1 and Tgfbr2, result in abnormal vascular development especially of the yolk sac, leading to embryonic lethality. There are significant differences between murine and primate development that limit interpretation of studies from mouse models. Thus, to examine the role of TGFβ in early human vascular development we used the model of differentiating human embryonic stem cell-derived embryoid bodies to recapitulate early stages of embryonic development. TGFβ was applied for different time frames after initiation of embryoid body cultures to assess its effect on differentiation. TGFβ inhibited the expression of endodermal, endothelial and hematopoietic markers, which contrasts with findings in the mouse in which TGFβ reduced the level of endodermal markers but increased endothelial marker expression. The inhibition observed was not due to changes in proliferation or apoptosis. This marked contrast between the two species may reflect the different origins of the yolk sac hemangiogenic lineages in mouse and human. TGFβ effects on the hypoblast, from which these cell lineages are derived in human, would decrease subsequent differentiation of hematopoietic, endothelial and endodermal cells. By contrast, TGFβ action on murine hypoblast, while affecting endoderm would not affect the hemangiogenic lineages that are epiblast-derived in the mouse. This study highlights important differences between early human and mouse embryonic development and suggests a role of TGFβ in human hypoblast differentiation.

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The role of TGF‐βs in mammalian development and neoplasia

Cited by 27 publications

References 22 publications

Expression of Adrenomedullin and Its Receptor during Embryogenesis Suggests Autocrine or Paracrine Modes of Action

Expression of Adrenomedullin and Its Receptor during Embryogenesis Suggests Autocrine or Paracrine Modes of Action

Transforming growth factor‐β in the early mouse embryo: Implications for the regulation of muscle formation and implantation

TGFβ inhibition of yolk-sac-like differentiation of human embryonic stem-cell-derived embryoid bodies illustrates differences between early mouse and human development

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