scholarly journals Synergistic interaction between the fibroblast growth factor and bone morphogenetic protein signaling pathways in lens cells

2015 ◽  
Vol 26 (13) ◽  
pp. 2561-2572 ◽  
Author(s):  
Bruce A. Boswell ◽  
Linda S. Musil
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Bone Morphogenetic Protein ◽  
Primary Cultures ◽  
Bmp Signaling ◽  
Fibroblast Growth ◽  
Lens Development ◽  
Morphogenetic Protein ◽  
Lens Cells ◽  
And Function

Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency—fiber cell differentiation and gap junction–mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for 6 d with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK-independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF promotes expression of BMP target genes as well as of BMP4. Together these studies reveal a novel mode of cooperation between the FGF and BMP pathways in which BMP keeps lens cells in an optimally FGF-responsive state and, reciprocally, FGF enhances BMP-mediated gene expression. This interaction provides a mechanistic explanation for why disruption of either FGF or BMP signaling in the lens leads to defects in lens development and function.

scholarly journals Responses of Epibranchial Placodes to Disruptions of the FGF and BMP Signaling Pathways in Embryonic Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Stefan Washausen ◽  
Wolfgang Knabe
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Receptor Subtypes ◽  
Fibroblast Growth ◽  
Morphogenetic Protein ◽  
High Doses ◽  
Epibranchial Placodes

Placodes are ectodermal thickenings of the embryonic vertebrate head. Their descendants contribute to sensory organ development, but also give rise to sensory neurons of the cranial nerves. In mammals, the signaling pathways which regulate the morphogenesis and neurogenesis of epibranchial placodes, localized dorsocaudally to the pharyngeal clefts, are poorly understood. Therefore, we performed mouse whole embryo culture experiments to assess the impact of pan-fibroblast growth factor receptor (FGFR) inhibitors, anti-FGFR3 neutralizing antibodies or the pan-bone morphogenetic protein receptor (BMPR) inhibitor LDN193189 on epibranchial development. We demonstrate that each of the three paired epibranchial placodes is regulated by a unique combination of FGF and/or bone morphogenetic protein (BMP) signaling. Thus, neurogenesis depends on fibroblast growth factor (FGF) signals, albeit to different degrees, in all epibranchial placodes (EP), whereas only EP1 and EP3 significantly rely on neurogenic BMP signals. Furthermore, individual epibranchial placodes vary in the extent to which FGF and/or BMP signals (1) have access to certain receptor subtypes, (2) affect the production of Neurogenin (Ngn)2+ and/or Ngn1+ neuroblasts, and (3) regulate either neurogenesis alone or together with structural maintenance. In EP2 and EP3, all FGF-dependent production of Ngn2+ neuroblasts is mediated via FGFR3 whereas, in EP1, it depends on FGFR1 and FGFR3. Differently, production of FGF-dependent Ngn1+ neuroblasts almost completely depends on FGFR3 in EP1 and EP2, but not in EP3. Finally, FGF signals turned out to be responsible for the maintenance of both placodal thickening and neurogenesis in all epibranchial placodes, whereas administration of the pan-BMPR inhibitor, apart from its negative neurogenic effects in EP1 and EP3, causes only decreases in the thickness of EP3. Experimentally applied inhibitors most probably not only blocked receptors in the epibranchial placodes, but also endodermal receptors in the pharyngeal pouches, which act as epibranchial signaling centers. While high doses of pan-FGFR inhibitors impaired the development of all pharyngeal pouches, high doses of the pan-BMPR inhibitor negatively affected only the pharyngeal pouches 3 and 4. In combination with partly concordant, partly divergent findings in other vertebrate classes our observations open up new approaches for research into the complex regulation of neurogenic placode development.

scholarly journals BMP action in skeletogenesis involves attenuation of retinoid signaling

2006 ◽  
Vol 174 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Lisa M. Hoffman ◽  
Kamal Garcha ◽  
Konstantina Karamboulas ◽  
Matthew F. Cowan ◽  
Linsay M. Drysdale ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Organ Culture ◽  
Signaling Pathways ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Signaling Molecules ◽  
Bmp Signaling ◽  
Retinoid Signaling ◽  
Morphogenetic Protein ◽  
Bona Fide

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.

scholarly journals Loss of mismatch repair signaling impairs the WNT–bone morphogenetic protein crosstalk and the colonic homeostasis

2019 ◽  
Vol 12 (6) ◽  
pp. 410-423
Author(s):  
Katrine Nørgaard ◽  
Carolin Müller ◽  
Nadja Christensen ◽  
María L Chiloeches ◽  
Cesilie L Madsen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Mismatch Repair ◽  
Goblet Cells ◽  
Bmp Signaling ◽  
Colonic Epithelium ◽  
Signaling Crosstalk ◽  
Dna Mismatch ◽  
Morphogenetic Protein ◽  
And Function ◽  
Deficient Mice

Abstract The fine balance between proliferation, differentiation, and apoptosis in the colonic epithelium is tightly controlled by the interplay between WNT, Notch, and bone morphogenetic protein (BMP) signaling. How these complex networks coordinate the colonic homeostasis, especially if cancer predisposing mutations such as mutations in the DNA mismatch repair (MMR) are present, is unclear. Inactivation of the MMR system has long been linked to colorectal cancer; however, little is known about its role in the regulation of the colonic homeostasis. It has been shown that loss of MMR promotes the proliferation of colon epithelial cells that renders them highly susceptible to transformation. The mechanism through which MMR mediates this effect, yet, remains to be determined. Using an MMR-deficient mouse model, we show that increased methylation of Dickkopf1 impacts its expression, and consequently, the ability to negatively regulate WNT signaling. As a result, excessive levels of active β-catenin promote strong crypt progenitor-like phenotype and abnormal proliferation. Under these settings, the development and function of the goblet cells are affected. MMR-deficient mice have fewer goblet cells with enlarged mucin-loaded vesicles. We further show that MMR inactivation impacts the WNT–BMP signaling crosstalk.

scholarly journals P11.34 Bone Morphogenetic Protein 4 can sensitize glioblastoma cells to temozolomide

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii50-iii50
Author(s):  
I Verploegh ◽  
A Conidi ◽  
M Lamfers ◽  
C Dirven ◽  
S Leenstra ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Cell Lines ◽  
Combination Treatment ◽  
Methylation Status ◽  
Primary Cultures ◽  
Therapeutic Benefit ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 4 ◽  
Morphogenetic Protein ◽  
Significant Difference

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor. Its recurrence and resistance to current therapies, i.e. temozolomide (TMZ), is thought to result from a subpopulation of cells exhibiting stem cell properties, called glioblastoma stem-like cells (GSCs). Bone Morphogenetic Protein 4 (BMP4) induces GSCs differentiation, leading to a less resistant phenotype. In this study we show that co-treatment of BMP4 with TMZ has therapeutic benefit in a subset of GBM cell lines. Furthermore, we looked for patients’ molecular signatures that could predict sensitivity to this combination treatment. MATERIAL AND METHODS A panel of 17 primary GBM cultures (passages 5–10) were treated with increasing concentrations of TMZ, BMP4 and TMZ + BMP4 for 5 and 7 days and cell viability has been measured. The Combination Index (CI) of the two drugs was calculated to assess the response of each line to TMZ and BMP4 treatment. DNA was used to determine the MGMT promotor methylation status and for targeted exome sequencing. Expression levels of BMP signaling components and differentiation associated genes were determined by qPCR. RESULTS 12 cultures of primary GBMs and 5 cultures of recurrent GBMs were included. Overall, 71% of the tested cell lines was resistant to TMZ, while 41% was resistant to BMP4. Strikingly, 53% of primary cultures show synergy between TMZ and BMP4 (CI < 1 at a Fraction Affected of 50% (Fa50)). There was no significant difference in synergy between five or seven days of treatment. However, combination treatment of BMP4 and TMZ was more effective than sequential treatment. CONCLUSION Co-treatment of BMP4 and TMZ could be of therapeutic benefit in GBM patients, irrespective of their sensitivity to TMZ. Further research regarding the mechanism behind this synergy is necessary as to identify predictive markers for treatment response.

scholarly journals Estrogen Opposes the Apoptotic Effects of Bone Morphogenetic Protein 7 on Tissue Remodeling

2000 ◽  
Vol 20 (13) ◽  
pp. 4626-4634 ◽  
Author(s):  
David G. Monroe ◽  
Donald F. Jin ◽  
Michel M. Sanders
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Bone Morphogenetic Protein ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Bone Morphogenetic Protein 7 ◽  
Reproductive Tissues ◽  
Morphogenetic Protein ◽  
Estrogen Withdrawal

ABSTRACT Interactions between estrogen and growth factor signaling pathways at the level of gene expression play important roles in the function of reproductive tissues. For example, estrogen regulates transforming growth factor beta (TGFβ) in the uterus during the proliferative phase of the mammalian reproductive cycle. Bone morphogenetic protein 7 (BMP-7), a member of the TGFβ superfamily, is also involved in the development and function of reproductive tissues. However, relatively few studies have addressed the expression of BMP-7 in reproductive tissues, and the role of BMP-7 remains unclear. As part of an ongoing effort to understand how estrogen represses gene expression and to study its interactions with other signaling pathways, chick BMP-7 (cBMP-7) was cloned. cBMP-7 mRNA levels are repressed threefold within 8 h following estrogen treatment in the chick oviduct, an extremely estrogen-responsive reproductive tissue. This regulation occurs at the transcriptional level. Estrogen has a protective role in many tissues, and withdrawal from estrogen often leads to tissue regression; however, the mechanisms mediating regression of the oviduct remain unknown. Terminal transferase-mediated end-labeling and DNA laddering assays demonstrated that regression of the oviduct during estrogen withdrawal involves apoptosis, which is a novel observation. cBMP-7 mRNA levels during estrogen withdrawal increase concurrently with the apoptotic index of the oviduct. Furthermore, addition of purified BMP-7 induces apoptosis in primary oviduct cells. This report demonstrates that the function of BMP-7 in the oviduct involves the induction of apoptosis and that estrogen plays an important role in opposing this function.

scholarly journals Multiple Signaling Pathways Converge to Regulate Bone-Morphogenetic-Protein-Dependent Glial Gene Expression

2009 ◽  
Vol 31 (6) ◽  
pp. 473-486 ◽  
Author(s):  
Justin J. Dore ◽  
John C. DeWitt ◽  
Nithya Setty ◽  
Mareshia D. Donald ◽  
Esther Joo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Bone Morphogenetic Protein ◽  
Morphogenetic Protein ◽  
Multiple Signaling

scholarly journals Cross-Talk between Fibroblast Growth Factor and Bone Morphogenetic Proteins Regulates Gap Junction-mediated Intercellular Communication in Lens Cells

2008 ◽  
Vol 19 (6) ◽  
pp. 2631-2641 ◽  
Author(s):  
Bruce A. Boswell ◽  
Pamela J. Lein ◽  
Linda S. Musil
Keyword(s):  
Growth Factor ◽  
Gap Junction ◽  
Fibroblast Growth Factor ◽  
Cross Talk ◽  
Primary Cultures ◽  
Vitreous Body ◽  
Equatorial Region ◽  
Bmp Signaling ◽  
Fibroblast Growth ◽  
Lens Cells

Homeostasis in the lens is dependent on an extensive network of cell-to-cell gap junctional channels. Gap junction-mediated intercellular coupling (GJIC) is higher in the equatorial region of the lens than at either pole, an asymmetry believed essential for lens transparency. Primary cultures of embryonic chick lens epithelial cells up-regulate GJIC in response to purified fibroblast growth factor (FGF)1/2 or to medium conditioned by vitreous bodies, the major reservoir of factors (including FGF) for the lens equator. We show that purified bone morphogenetic protein (BMP)2, -4, and -7 also up-regulate GJIC in these cultures. BMP2, -4, or both are present in vitreous body conditioned medium, and BMP4 and -7 are endogenously expressed by lens cells. Remarkably, lens-derived BMP signaling is required for up-regulation of GJIC by purified FGF, and sufficient for up-regulation by vitreous humor. This is the first demonstration of an obligatory interaction between FGF and BMPs in postplacode lens cells, and of a role for FGF/BMP cross-talk in regulating GJIC in any cell type. Our results support a model in which the angular gradient in GJIC in the lens, and thus proper lens function, is dependent on signaling between the FGF and BMP pathways.

scholarly journals Bone Morphogenetic Protein Signaling Is Required for Maintenance of Differentiated Phenotype, Control of Proliferation, and Hypertrophy in Chondrocytes

1998 ◽  
Vol 140 (2) ◽  
pp. 409-418 ◽  
Author(s):  
Motomi Enomoto-Iwamoto ◽  
Masahiro Iwamoto ◽  
Yoshiki Mukudai ◽  
Yasuhiko Kawakami ◽  
Tsutomu Nohno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Collagen Gene ◽  
Type Ii ◽  
Type X Collagen ◽  
Bmp Receptors ◽  
Collagen Gene Expression ◽  
Morphogenetic Protein

To examine the role of bone morphogenetic protein (BMP) signaling in chondrocytes during endochondral ossification, the dominant negative (DN) forms of BMP receptors were introduced into immature and mature chondrocytes isolated from lower and upper portions of chick embryo sternum, respectively. We found that control sternal chondrocyte populations expressed type IA, IB, and II BMP receptors as well as BMP-4 and -7. Expression of a DN-type II BMP receptor (termed DN-BMPR-II) in immature lower sternal (LS) chondrocytes led to a loss of differentiated functions; compared with control cells, the DN-BMPR- II–expressing LS chondrocytes proliferated more rapidly, acquired a fibroblastic morphology, showed little expression of type II collagen and aggrecan genes, and upregulated type I collagen gene expression. Expression of DN-BMPR-II in mature hypertrophic upper sternal (US) chondrocytes caused similar effects. In addition, the DN-BMPR-II–expressing US cells exhibited little alkaline phosphatase activity and type X collagen gene expression, while the control US cells produced both alkaline phosphatase and type X collagen. Both DN-BMPR-II–expressing US and LS chondrocytes failed to respond to treatment with BMP-2 . When we examined the effects of DN forms of types IA and IB BMP receptors, we found that DN-BMPR-IA had little effect, while DN-BMPR-IB had similar but weaker effects compared with those of DN-BMPR-II. We conclude that BMP signaling, particularly that mediated by the type II BMP receptor, is required for maintenance of the differentiated phenotype, control of cell proliferation, and expression of hypertrophic phenotype.

Sign in / Sign up

Export Citation Format

Share Document