scholarly journals Quantitative Imaging in Whole-mount Zebrafish Embryos Traces Morphogen Gradient Maintenance and Noise Propagation in BMP Signaling

2021 ◽  
Author(s):  
Xu Wang ◽  
Linlin Li ◽  
Ye Bu ◽  
Yixuan Liu ◽  
Tzu-Ching Wu ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Single Molecule ◽  
Zebrafish Embryo ◽  
Quantitative Imaging ◽  
Bmp Signaling ◽  
Morphogen Gradient ◽  
Nodal Signaling ◽  
Embryonic Patterning ◽  
Whole Mount ◽  
Development Data

Abstract Dorsoventral (DV) embryonic patterning relies on precisely controlled interpretation of morphogen signaling. In all vertebrates, DV axis specification is informed by gradients of bone morphogenetic proteins (BMPs). We developed a 3D single-molecule mRNA quantification method in whole-mount zebrafish to quantify the inputs and outputs in this pathway. In combination with 3D computational modeling of zebrafish embryo development, data from this method revealed that sizzled (Szl), shaped by BMP and Nodal signaling, maintained a consistent inhibition level with chordin (Chd) to maintain the BMP morphogen gradient. Intriguingly, intrinsic BMP morphogen expression is highly noisy at the ventral marginal layer in the early zebrafish gastrula, where the gradient for DV patterning is established, which implies an unexpected role for noise in gradient shaping.

scholarly journals Quantitative imaging in whole-mount zebrafish embryos traces morphogen gradient maintenance and noise propagation in BMP signaling

2021 ◽  
Author(s):  
Xu Wang ◽  
Linlin Li ◽  
Ye Bu ◽  
Yixuan Liu ◽  
Tzu-Ching Wu ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Single Molecule ◽  
Zebrafish Embryo ◽  
Quantitative Imaging ◽  
Bmp Signaling ◽  
Morphogen Gradient ◽  
Nodal Signaling ◽  
Embryonic Patterning ◽  
Whole Mount ◽  
Development Data

Dorsoventral (DV) embryonic patterning relies on precisely controlled interpretation of morphogen signaling. In all vertebrates, DV axis specification is informed by gradients of Bone Morphogenetic Proteins (BMPs). We developed a 3D single-molecule mRNA quantification method in whole-mount zebrafish to quantify the inputs and outputs in this pathway. In combination with 3D computational modeling of zebrafish embryo development, data from this method revealed that Sizzled (Szl), shaped by BMP and Nodal signaling, kept a consistent inhibition level with Chordin (Chd) to maintain the BMP morphogen gradient. Intriguingly, BMP morphogen intrinsic expression is highly noisy at the ventral marginal layer in early zebrafish gastrula, where the gradient for DV patterning is established, which implies an unexpected role for noise in gradient shaping.

scholarly journals Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo

2019 ◽  
Author(s):  
Linlin Li ◽  
Xu Wang ◽  
Mary C. Mullins ◽  
David M. Umulis
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Zebrafish Embryo ◽  
Three Dimensional ◽  
Bmp Signaling ◽  
Multiple Time ◽  
Blastula Stage ◽  
Starting Point ◽  
Gene And Protein Expression ◽  
Multiple Time Points ◽  
Source Sink

AbstractBone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however it is not clear how the source-sink mechanism shapes patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo. We propose a new three-dimensional growing Partial Differential Equation (PDE)-based model to simulate the BMP patterning process during the blastula stage. This model provides a starting point to elucidate how different mechanisms and components work together in 3D to create and maintain the BMP gradient in the embryo. We also show how the 3D model fits the BMP signaling gradient data at multiple time points along both axes. Furthermore, sensitivity analysis of the model suggests that the spatiotemporal patterns of Chordin and BMP ligand gene expression are dominant drivers of shape in 3D and more work is needed to quantify the spatiotemporal profiles of gene and protein expression to further refine the models.

BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3421-3429
Author(s):  
Thomas Schlange ◽  
Hans-Henning Arnold ◽  
Thomas Brand
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Target Genes ◽  
Bmp Signaling ◽  
Paraxial Mesoderm ◽  
Axis Formation ◽  
Nodal Signaling ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Positive Regulator ◽  
The Right

A model of left-right axis formation in the chick involves inhibition of bone morphogenetic proteins by the antagonist Car as a mechanism of upregulating Nodal in the left lateral plate mesoderm. By contrast, expression of CFC, a competence factor, which is absolutely required for Nodal signaling in the lateral plate mesoderm is dependent on a functional BMP signaling pathway. We have therefore investigated the relationship between BMP and Nodal in further detail. We implanted BMP2 and Noggin-expressing cells into the left lateral plate and paraxial mesoderm and observed a strong upregulation of Nodal and its target genes Pitx2 and Nkx3.2. In addition Cfc, the Nodal type II receptor ActrIIa and Snr were found to depend on BMP signaling for their expression. Comparison of the expression domains of Nodal, Bmp2, Car and Cfc revealed co-expression of Nodal, Cfc and Bmp2, while Car and Nodal only partially overlapped. Ectopic application of BMP2, Nodal, and Car as well as combinations of this signaling molecules to the right lateral plate mesoderm revealed that BMP2 and Car need to synergize in order to specify left identity. We propose a novel model of left-right axis formation, which involves BMP as a positive regulator of Nodal signaling in the chick embryo.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

scholarly journals Bone Morphogenetic Proteins and Diabetic Retinopathy

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 593
Author(s):  
Khaled Elmasry ◽  
Samar Habib ◽  
Mohamed Moustafa ◽  
Mohamed Al-Shabrawey
Keyword(s):  
Diabetic Retinopathy ◽  
Bone Morphogenetic Proteins ◽  
Potential Role ◽  
Microvascular Dysfunction ◽  
Cardiovascular Complications ◽  
Bmp Signaling ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Inflammation ◽  
Underlying Mechanisms

Bone morphogenetic proteins (BMPs) play an important role in bone formation and repair. Recent studies underscored their essential role in the normal development of several organs and vascular homeostasis in health and diseases. Elevated levels of BMPs have been linked to the development of cardiovascular complications of diabetes mellitus. However, their particular role in the pathogenesis of microvascular dysfunction associated with diabetic retinopathy (DR) is still under-investigated. Accumulated evidence from our and others’ studies suggests the involvement of BMP signaling in retinal inflammation, hyperpermeability and pathological neovascularization in DR and age-related macular degeneration (AMD). Therefore, targeting BMP signaling in diabetes is proposed as a potential therapeutic strategy to halt the development of microvascular dysfunction in retinal diseases, particularly in DR. The goal of this review article is to discuss the biological functions of BMPs, their underlying mechanisms and their potential role in the pathogenesis of DR in particular.

BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4523-4534 ◽  
Author(s):  
Eleonora Minina ◽  
Hans Markus Wenzel ◽  
Conny Kreschel ◽  
Seth Karp ◽  
William Gaffield ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Feedback Loop ◽  
Bmp Signaling ◽  
Signaling Systems ◽  
Chondrocyte Maturation ◽  
Parathyroid Hormone Related Protein ◽  
Proliferation And Differentiation ◽  
Mouse Limb ◽  
Pthrp Expression

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of Ihh. Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.

BMP Signaling in Regenerative Medicine

2013 ◽  
pp. 1-30
Author(s):  
Julia Zimmer ◽  
Elisa Degenkolbe ◽  
Britt Wildemann ◽  
Petra Seemann
Keyword(s):  
Cardiovascular Disease ◽  
Bone Morphogenetic Proteins ◽  
Tissue Regeneration ◽  
Cancer Diagnosis ◽  
Bone Growth ◽  
Clinical Applications ◽  
Bmp Signaling ◽  
Non Union ◽  
Connective Tissue Regeneration ◽  
Growth Induction

More than 40 years after the discovery of Bone Morphogenetic Proteins (BMPs) as bone inducers, a whole protein family of growth factors connected to a wide variety of functions in embryonic development, homeostasis, and regeneration has been characterized. Today, BMP2 and BMP7 are already used in the clinic to promote vertebral fusions and restoration of non-union fractures. Besides describing present clinical applications, the authors review ongoing trials highlighting the future possibilities of BMPs in medicine. Apparently, the physiological roles of BMPs have expanded their range from bone growth induction and connective tissue regeneration to cancer diagnosis/treatment and cardiovascular disease prevention.

BMP Signaling in Regenerative Medicine

2013 ◽  
pp. 1252-1281
Author(s):  
Julia Zimmer ◽  
Elisa Degenkolbe ◽  
Britt Wildemann ◽  
Petra Seemann
Keyword(s):  
Cardiovascular Disease ◽  
Bone Morphogenetic Proteins ◽  
Tissue Regeneration ◽  
Cancer Diagnosis ◽  
Bone Growth ◽  
Clinical Applications ◽  
Bmp Signaling ◽  
Non Union ◽  
Connective Tissue Regeneration ◽  
Growth Induction

More than 40 years after the discovery of Bone Morphogenetic Proteins (BMPs) as bone inducers, a whole protein family of growth factors connected to a wide variety of functions in embryonic development, homeostasis, and regeneration has been characterized. Today, BMP2 and BMP7 are already used in the clinic to promote vertebral fusions and restoration of non-union fractures. Besides describing present clinical applications, the authors review ongoing trials highlighting the future possibilities of BMPs in medicine. Apparently, the physiological roles of BMPs have expanded their range from bone growth induction and connective tissue regeneration to cancer diagnosis/treatment and cardiovascular disease prevention.

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