Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development

Development ◽  
1991 ◽  
Vol 113 (3) ◽  
pp. 867-878 ◽  
Author(s):  
S.D. Robinson ◽  
G.B. Silberstein ◽  
A.B. Roberts ◽  
K.C. Flanders ◽  
C.W. Daniel
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Slow Release ◽  
Mouse Mammary Gland ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Beta 2

Transforming Growth Factor-beta 1 (TGF-beta 1) was previously shown to inhibit reversibly the growth of mouse mammary ducts when administered in vivo by miniature slow-release plastic implants. We now report a comparative analysis of three TGF-beta isoforms with respect to gene expression and localization of protein products within the mouse mammary gland. Our studies revealed overlapping expression patterns of TGF-beta 1, TGF-beta 2 and TGF-beta 3 within the epithelium of the actively-growing mammary end buds during branching morphogenesis, as well as within the epithelium of growth-quiescent ducts. However, TGF-beta 3 was the only isoform detected in myoepithelial progenitor cells (cap cells) of the growing end buds and myoepithelial cells of the mature ducts. During pregnancy, TGF-beta 2 and TGF-beta 3 transcripts increased to high levels, in contrast to TGF-beta 1 transcripts which were moderately abundant; TGF-beta 2 was significantly transcribed only during pregnancy. Molecular hybridization in situ revealed overlapping patterns of expression for the three TGF-beta isoforms during alveolar morphogenesis, but showed that, in contrast to the patterns of TGF-beta 1 and TGF-beta 2 expression, TGF-beta 3 is expressed more heavily in ducts than in alveoli during pregnancy. Developing alveolar tissue and its associated ducts displayed striking TGF-beta 3 immunoreactivity which was greatly reduced during lactation. All three isoforms showed dramatically reduced expression in lactating tissue. The biological effects of active, exogenous TGF-beta 2 and TGF-beta 3 were tested with slow-release plastic implants. These isoforms, like TGF-beta 1, inhibited mammary ductal elongation in situ by causing the disappearance of the proliferating stem cell layer (cap cells) and rapid involution of ductal end buds. None of the isoforms were active in inhibiting alveolar morphogenesis. We conclude that under the limited conditions of these tests, the three mammalian isoforms are functionally equivalent. However, striking differences in patterns of gene expression and in the distribution of immunoreactive peptides suggest that TGF-beta isoforms may have distinct roles in mammary growth regulation, morphogenesis and functional differentiation.

Expression of transforming growth factor beta 2 RNA during murine embryogenesis

Development ◽  
1989 ◽  
Vol 106 (4) ◽  
pp. 759-767 ◽  
Author(s):  
R.W. Pelton ◽  
S. Nomura ◽  
H.L. Moses ◽  
B.L. Hogan
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Post Partum ◽  
Mouse Embryos ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Beta 2 ◽  
Temporal And Spatial

We have studied the temporal and spatial expression of transforming growth factor beta 2 (TGF beta 2) RNA in mouse embryos from 10.5 days post coitum (p.c.) to 3 days post partum (p.p.) by in situ hybridization analysis. TGF beta 2 RNA is expressed in a variety of tissues including bone, cartilage, tendon, gut, blood vessels, skin and fetal placenta, and is in general found in the mesenchymal component of these tissues. The expression of TGF beta 2 RNA changes during development in a manner consistent with a role for the gene product in mediating mesenchymal-epithelial interactions.

scholarly journals TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy.

1993 ◽  
Vol 120 (1) ◽  
pp. 245-251 ◽  
Author(s):  
S D Robinson ◽  
A B Roberts ◽  
C W Daniel
Keyword(s):  
Mammary Gland ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Milk Proteins ◽  
Tgf Beta ◽  
Pregnant Mice ◽  
Growth Factor Beta ◽  
Beta 2 ◽  
Dose Dependent ◽  
Casein Synthesis

Mammary explants from 14-15-d-pregnant mice synthesize and secrete milk proteins in culture in response to insulin, hydrocortisone, and prolactin. Here we demonstrate that transforming growth factor beta (TGF beta) treatment suppresses, in a dose dependent and reversible manner, the ability of explants to synthesize and secrete milk caseins. TGF beta does not affect the level of casein mRNA within explants but inhibits casein synthesis posttranscriptionally. We also show increased expression of TGF beta 2 and TGF beta 3 in intact mammary gland as pregnancy progresses, with reduced expression of all three TGF betas at the onset of lactation. These findings suggest that endogenously produced TGF beta may limit the accumulation of milk caseins that are produced in the mammary gland during pregnancy.

Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring

1995 ◽  
Vol 108 (3) ◽  
pp. 985-1002 ◽  
Author(s):  
M. Shah ◽  
D.M. Foreman ◽  
M.W. Ferguson
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Collagen I ◽  
Tgf Beta ◽  
Early Stages ◽  
Collagen Iii ◽  
Exogenous Addition ◽  
Growth Factor Beta ◽  
Beta 2

Exogenous addition of neutralising antibody to transforming growth factor-beta 1,2 to cutaneous wounds in adult rodents reduces scarring. Three isoforms of transforming growth factor-beta (1, 2 and 3) have been identified in mammals. We investigated the isoform/isoforms of TGF-beta responsible for cutaneous scarring by: (i) reducing specific endogenous TGF-beta isoforms by exogenous injection of isoform specific neutralising antibodies; and (ii) increasing the level of specific TGF-beta isoforms by exogenous infiltration into the wound margins. Exogenous addition of neutralising antibody to TGF-beta 1 plus neutralising antibody to TGF-beta 2 reduced the monocyte and macrophage profile, neovascularisation, fibronectin, collagen III and collagen I deposition in the early stages of wound healing compared to control wounds. Treatment with neutralising antibodies to TGF-betas 1 and 2 markedly improved the architecture of the neodermis to resemble that of normal dermis and reduced scarring while the control wounds healed with scar formation. Exogenous addition of neutralising antibody to TGF-beta 1 alone also reduced the monocyte and macrophage profile, fibronectin, collagen III and collagen I deposition compared to control wounds. However, treatment with neutralising antibody to TGF-beta 1 alone only marginally reduced scarring. By contrast, wounds treated with neutralising antibody to TGF-beta 2 alone did not differ from control wounds. Interestingly, exogenous addition of the TGF-beta 3 peptide also reduced the monocyte and macrophage profile, fibronectin, collagen I and collagen III deposition in the early stages of wound healing and markedly improved the architecture of the neodermis and reduced scarring. By contrast, wounds treated with either TGF-beta 1 or with TGF-beta 2 had more extracellular matrix deposition in the early stages of wound healing but did not differ from control wounds in the final quality of scarring. This study clearly demonstrates isoform specific differences in the role of TGF-betas in wound healing and cutaneous scarring. TGF-beta 1 and TGF-beta 2 are implicated in cutaneous scarring. This study also suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.

scholarly journals Expression of mRNA for IL1 beta, IL6 and TGF beta 1 in developing human bone and cartilage.

1994 ◽  
Vol 42 (6) ◽  
pp. 733-744 ◽  
Author(s):  
R A Dodds ◽  
K Merry ◽  
A Littlewood ◽  
M Gowen
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Close Association ◽  
Interleukin 1 ◽  
Cell Types ◽  
Tgf Beta ◽  
Specific Stage ◽  
Growth Factor Beta

Using in situ hybridization, we investigated the expression of mRNA for interleukin-1 beta (IL1 beta), interleukin-6 (IL6), and transforming growth factor-beta-1 (TGF beta 1) in sections of developing bone in human osteophytes. The expression was related to the cellular activity of alkaline phosphatase to aid in the identification of pre-osteoblast populations. IL1 beta mRNA was localized in active osteoblasts within distinct areas of intramembranous ossification. However, the expression was sporadic and appeared to occur at a specific stage of the osteoblast life cycle. There was no IL1 beta mRNA expression in any cell types during endochondral ossification. IL6 mRNA expression was located within pre-osteoblasts and in newly differentiated and matrix-secreting osteoblasts; expression was absent or reduced in flattened, inactive osteoblasts. Weak or no IL6 expression was observed in chondroblasts and chondrocytes, respectively. However, there was a close association between IL6 mRNA expression and the differentiation of mesenchymal cells into osteoblasts. TGF beta 1 expression was localized to osteoblasts apposed to bone or cartilage matrix; the intensity of expression correlated with matrix secretion. Chondroblasts and chondrocytes expressed lower but significant levels of TGF beta 1 mRNA; the expression was lost with the progression to calcifying cartilage. The three cytokines studied were differentially expressed both temporally and spatially, suggesting different roles for each in osteoblast and chondrocyte function.

scholarly journals Synthesis of transforming growth factor-beta 1 by megakaryocytes and its localization to megakaryocyte and platelet alpha-granules

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 1946-1955 ◽  
Author(s):  
RA Fava ◽  
TT Casey ◽  
J Wilcox ◽  
RW Pelton ◽  
HL Moses ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Immunoperoxidase Technique ◽  
Storage Site ◽  
Tgf Beta ◽  
Growth Factor Beta

We have directly demonstrated that megakaryocytes are a major site of synthesis and storage of transforming growth factor-beta 1 (TGF/beta 1) by combined immunohistochemical, immunocytochemical, and in situ hybridization methods. The presence of TGF/beta 1 messenger RNA (mRNA) in mature megakaryocytes in adult rat spleen and bone marrow (BM) was established by in situ hybridization. Localization of TGF/beta 1 protein to intact alpha-granules of megakaryocytes, its putative storage site, was accomplished in glycol-methacrylate embedded porcine BM with an immunoperoxidase technique and light microscopy. The TGF/beta 1 was sequestered in intracytoplasmic granules in a pattern virtually identical to that of another alpha-granule marker protein, fibrinogen. This observation strongly suggests packaging of TGF/beta 1 into this organelle within megakaryocytes. That TGF/beta 1 mRNA was localized to megakaryocytes suggests that the TGF/beta 1 found in the alpha-granules in platelets originates with megakaryocyte synthesis. The alpha-granule localization of TGF/beta 1, as well as fibrinogen, was also demonstrated in isolated platelets at the ultrastructural level by electronmicroscopy (EM) and postembedding colloidal-gold immunocytochemistry, thus directly demonstrating that alpha-granules are the final storage site for TGF/beta 1 in mature platelets.

scholarly journals Bidirectional effects of transforming growth factor beta (TGF-beta) on colony-stimulating factor-induced human myelopoiesis in vitro: differential effects of distinct TGF-beta isoforms

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2239-2247 ◽  
Author(s):  
SE Jacobsen ◽  
JR Keller ◽  
FW Ruscetti ◽  
P Kondaiah ◽  
AB Roberts ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Hematopoietic Progenitor Cells ◽  
Colony Stimulating Factor ◽  
Tgf Beta ◽  
Hematopoietic Progenitor ◽  
Growth Factor Beta ◽  
Beta 2 ◽  
Macrophage Colony ◽  
Stimulating Factor

Transforming growth factor-beta (TGF-beta) has potent antiproliferative effects on human hematopoietic progenitor cells. We report here that TGF-beta 1 and -beta 2 also exert bimodal dose-dependent stimulation of granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte- CSF-induced day 7 granulocyte-macrophage colony-forming units. This increase in colony formation was restricted to low doses (0.01 to 1.0 ng/mL) of TGF-beta 1 and was due to increased granulopoiesis, showing that TGF-beta can affect the differentiation as well as the proliferation of hematopoietic progenitors. Furthermore, TGF-beta 3 was found to be a more potent inhibitor of hematopoietic progenitor cells than TGF-beta 1 and -beta 2. In contrast to the bidirectional proliferative effects of TGF-beta 1 and -beta 2, the effects of TGF- beta 3 on human hematopoiesis were only inhibitory, showing for the first time that TGF-beta isoforms differ not only in potencies but also with regard to the nature of the response they elicit.

Transcriptional modulation of transin gene expression by epidermal growth factor and transforming growth factor beta

1988 ◽  
Vol 8 (6) ◽  
pp. 2479-2483
Author(s):  
C M Machida ◽  
L L Muldoon ◽  
K D Rodland ◽  
B E Magun
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Prolonged Treatment ◽  
Transcriptional Level ◽  
Tgf Beta ◽  
Epidermal Growth ◽  
Growth Factor Beta

Transin is a transformation-associated gene which is expressed constitutively in rat fibroblasts transformed by a variety of oncogenes and in malignant mouse skin carcinomas but not benign papillomas or normal skin. It has been demonstrated that, in nontransformed Rat-1 cells, transin RNA expression is modulated positively by epidermal growth factor (EGF) and negatively by transforming growth factor beta (TGF-beta); other peptide growth factors were found to have no effect on transin expression. Results presented here indicate that both protein synthesis and continuous occupancy of the EGF receptor by EGF were required for sustained induction of transin RNA. Treatment with TGF-beta inhibited the ability of EGF to induce transin, whether assayed at the transcriptional level by nuclear run-on analysis or at the level of transin RNA accumulation by Northern (RNA) blot analysis of cellular RNA. TGF-beta both blocked initial induction of transin transcription by EGF and halted established production of transin transcripts during prolonged treatment. These results suggest that TGF-beta acts at the transcriptional level to antagonize EGF-mediated induction of transin gene expression.

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