scholarly journals Dynamic 3D tissue architecture directs BMP morphogen signaling during Drosophila wing morphogenesis

2018 ◽  
Author(s):  
Jinghua Gui ◽  
Yunxian Huang ◽  
Martin Kracklauer ◽  
Daniel Toddie-Moore ◽  
Kenji Kikushima ◽  
...  
Keyword(s):  
Growth Factor ◽  
Morphological Changes ◽  
Three Dimensional ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Extracellular Signaling ◽  
Morphogenetic Protein ◽  
Pupal Wing ◽  
3D Architecture ◽  
Wing Morphogenesis

SummaryAt the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how Decapentaplegic (Dpp) / Bone Morphogenetic Protein (BMP) signaling and 3D wing morphogenesis are coupled. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia directs the spatial distribution of BMP signaling, revealing how 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.

scholarly journals Coupling between dynamic 3D tissue architecture and BMP morphogen signaling duringDrosophilawing morphogenesis

2019 ◽  
Vol 116 (10) ◽  
pp. 4352-4361 ◽  
Author(s):  
Jinghua Gui ◽  
Yunxian Huang ◽  
Martin Montanari ◽  
Daniel Toddie-Moore ◽  
Kenji Kikushima ◽  
...  
Keyword(s):  
Growth Factor ◽  
Morphological Changes ◽  
Three Dimensional ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Extracellular Signaling ◽  
Morphogenetic Protein ◽  
Tightly Coupled ◽  
Pupal Wing ◽  
3D Architecture

At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using theDrosophilapupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2657-2665 ◽  
Author(s):  
Katarzyna Mleczko-Sanecka ◽  
Guillem Casanovas ◽  
Anan Ragab ◽  
Katja Breitkopf ◽  
Alexandra Müller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Iron Metabolism ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Protein

Abstract Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.

scholarly journals Graphene Oxide reinforced Agarose-Hydroxyapatite Bioprinted 3-D Scaffolds for Bone Regeneration

2021 ◽  
Author(s):  
Umakant Yadav
Keyword(s):  
Graphene Oxide ◽  
Cellular Differentiation ◽  
Morphological Changes ◽  
Three Dimensional ◽  
Human Mesenchymal Stem Cells ◽  
3D Bioprinting ◽  
Promising Strategy ◽  
Morphogenetic Protein ◽  
Enhanced Expression ◽  
3D Printed

Three-dimensional (3D) bioprinting is an emerging technology for fabricating cells, biomaterials and extracellular matrix (ECM) into customized shapes and patterns. Here, we report additive manufacturing to create a customized 3D bioactive constructs for regenerative medicine. We have attempted to emphasize the use of agarose and graphene oxide as a promising material for the conceptualization of bioink unpaid to its unique physicochemical properties. The 3D printed structure is able to regenerating bone tissues and regulates the cellular differentiation without any significant morphological changes. The presence of graphene oxide enhances the osteoinductive behavior of the developed scaffolds, which is further supplemented by encapsulating human mesenchymal stem cells (hMSCs) on the 3D printed scaffolds. A significant enhanced expression of early osteogenic markers like morphogenetic protein (BMP), Runx-2, collagen-1, osteopontin, osteocalcin as well as mineralized ECM are observed on agarose-hydroxyapatite and graphene oxide 3D printed scaffolds compared to agarose-hydroxyapatite 3D printed scaffolds. Thus, the outcomes of the developed 3D bioprinted scaffolds provide a promising strategy for development of personalized bone grafts for tissue regeneration.

scholarly journals It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1965 ◽  
Author(s):  
Christian Hiepen ◽  
Paul-Lennard Mendez ◽  
Petra Knaus
Keyword(s):  
Shear Stress ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Research Field ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Mechanical Stimuli ◽  
Signaling Crosstalk

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing research field. In bone, the tissue in which BMPs were first discovered, crosstalk of TGFβ/BMP signaling with mechanobiology is well understood. Likewise, the endothelium represents a tissue that is constantly exposed to multiple mechanical triggers, such as wall shear stress, elicited by blood flow or strain, and tension from the surrounding cells and to the extracellular matrix. To integrate mechanical stimuli, the cytoskeleton plays a pivotal role in the transduction of these forces in endothelial cells. Importantly, mechanical forces integrate on several levels of the TGFβ/BMP pathway, such as receptors and SMADs, but also global cell-architecture and nuclear chromatin re-organization. Here, we summarize the current literature on crosstalk mechanisms between biochemical cues elicited by TGFβ/BMP growth factors and mechanical cues, as shear stress or matrix stiffness that collectively orchestrate endothelial function. We focus on the different subcellular compartments in which the forces are sensed and integrated into the TGFβ/BMP growth factor signaling.

dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp

Development ◽  
1997 ◽  
Vol 124 (20) ◽  
pp. 4113-4120 ◽  
Author(s):  
S.M. Jackson ◽  
H. Nakato ◽  
M. Sugiura ◽  
A. Jannuzi ◽  
R. Oakes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Cellular Responses ◽  
Growth Factor Signaling ◽  
Tgf Beta ◽  
Morphogenetic Protein

Decapentaplegic (Dpp) is a Drosophila member of the Transforming Growth Factor-beta (TGF-beta)/Bone Morphogenetic Protein (BMP) superfamily of growth factors. Dpp serves as a classical morphogen, where concentration gradients of this secreted factor control patterning over many cell dimensions. Regulating the level of Dpp signaling is therefore critical to its function during development. One type of molecule proposed to modulate growth factor signaling at the cell surface are integral membrane proteoglycans. We show here that division abnormally delayed (dally), a Drosophila member of the glypican family of integral membrane proteoglycans is required for normal Dpp signaling during development, affecting cellular responses to this morphogen. Ectopic expression of dally+ can alter the patterning activity of Dpp, suggesting a role for dally+ in modulating Dpp signaling strength. These findings support a role for members of the glypican family in controlling TGF-beta/BMP activity in vivo by affecting signaling at the cell surface.

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 ALMS1 Regulates TGF-β Signaling and Morphology of Primary Cilia

2021 ◽  
Vol 9 ◽  
Author(s):  
María Álvarez-Satta ◽  
Mauro Lago-Docampo ◽  
Brais Bea-Mascato ◽  
Carlos Solarat ◽  
Sheila Castro-Sánchez ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Line ◽  
Transforming Growth Factor Beta ◽  
Primary Cilia ◽  
Transforming Growth Factor ◽  
Cellular Signaling ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Growth Factor Beta

In this study, we aimed to evaluate the role of ALMS1 in the morphology of primary cilia and regulation of cellular signaling using a knockdown model of the hTERT-RPE1 cell line. ALMS1 depletion resulted in the formation of longer cilia, which often displayed altered morphology as evidenced by extensive twisting and bending of the axoneme. Transforming growth factor beta/bone morphogenetic protein (TGF-β/BMP) signaling, which is regulated by primary cilia, was similarly affected by ALMS1 depletion as judged by reduced levels of TGFβ-1-mediated activation of SMAD2/3. These results provide novel information on the role of ALMS1 in the function of primary cilia and processing of cellular signaling, which when aberrantly regulated may underlie Alström syndrome.

The β1-integrin plays a key role in LEC invasion in an optimized 3-D collagen matrix model

2020 ◽  
Vol 319 (6) ◽  
pp. C1045-C1058
Author(s):  
Subhashree Kumaravel ◽  
Colette A. Abbey ◽  
Kayla J. Bayless ◽  
Sanjukta Chakraborty
Keyword(s):  
Growth Factor ◽  
Synergistic Effects ◽  
Three Dimensional ◽  
Lymphatic Vessels ◽  
Collagen Matrix ◽  
Vegf Receptor ◽  
Growth Factor Signaling ◽  
Sphingosine 1 Phosphate ◽  
Sprout Formation

Lymphangiogenesis, or formation of new lymphatic vessels, is a tightly regulated process that is controlled by growth factor signaling and biomechanical cues. Lymphatic endothelial cells (LECs) undergo remodeling, migration, and proliferation to invade the surrounding extracellular matrix (ECM) during both physiological and pathological lymphangiogenesis. This study optimized conditions for an in vitro three-dimensional (3-D) collagen-based model that induced LEC invasion and recapitulated physiological formation of lymphatic capillaries with lumens. Invasion of LECs was enhanced in the presence of sphingosine 1-phosphate (S1P). Effects of various known lymphangiogenic factors, vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factor (bFGF), interleukin (IL)-8, and hepatocyte growth factor (HGF), were tested on LEC sprout formation synergistically with VEGF-C. Several of these growth factors significantly enhanced LEC invasion, and synergistic effects of some of these further enhanced the sprouting density and lumen volume. To determine the contribution of specific ECM components, we analyzed the expression of different integrin subunits. Basal expressions of the integrin α5- and integrin β1-subunits were high in LECs. The addition of fibronectin, which mediates cellular responses through these integrins, enhanced LEC sprouting density and sprout length dose-dependently. siRNA-mediated knockdown of the integrin β1-subunit suppressed LEC invasion and also inhibited VEGF receptor (VEGFR)3 and ERK activation. Furthermore, exposing LECs to the inflammatory mediator lipopolysaccharide (LPS) inhibited sprouting. This optimized model for LEC invasion includes S1P, VEGF-C, and fibronectin within a 3-D collagen matrix, along with VEGF-C, VEGF-A, bFGF, and HGF in the culture medium, and provides a useful tool to investigate the functional effect of various lymphangiogenic factors and inhibitors.

scholarly journals The calcium channel subunit α2δ-3 organizes synapses via an activity-dependent and autocrine BMP signaling pathway

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kendall M. Hoover ◽  
Scott J. Gratz ◽  
Nova Qi ◽  
Kelsey A. Herrmann ◽  
Yizhou Liu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Calcium Channel ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Structure And Function ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Activity State ◽  
And Function ◽  
Activity Dependent

AbstractSynapses are highly specialized for neurotransmitter signaling, yet activity-dependent growth factor release also plays critical roles at synapses. While efficient neurotransmitter signaling relies on precise apposition of release sites and neurotransmitter receptors, molecular mechanisms enabling high-fidelity growth factor signaling within the synaptic microenvironment remain obscure. Here we show that the auxiliary calcium channel subunit α2δ-3 promotes the function of an activity-dependent autocrine Bone Morphogenetic Protein (BMP) signaling pathway at the Drosophila neuromuscular junction (NMJ). α2δ proteins have conserved synaptogenic activity, although how they execute this function has remained elusive. We find that α2δ-3 provides an extracellular scaffold for an autocrine BMP signal, suggesting a mechanistic framework for understanding α2δ’s conserved role in synapse organization. We further establish a transcriptional requirement for activity-dependent, autocrine BMP signaling in determining synapse density, structure, and function. We propose that activity-dependent, autocrine signals provide neurons with continuous feedback on their activity state for modulating both synapse structure and function.

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