scholarly journals Diversity and robustness of bone morphogenetic protein pattern formation

Development ◽  
2021 ◽  
Vol 148 (7) ◽  
pp. dev192344
Author(s):  
Aasakiran Madamanchi ◽  
Mary C. Mullins ◽  
David M. Umulis
Keyword(s):  
Stem Cell ◽  
Pattern Formation ◽  
Bone Morphogenetic Proteins ◽  
Spatial Scales ◽  
Protein Pattern ◽  
Dominant Role ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Reliable Performance ◽  
Cell Niche

ABSTRACTPattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many temporal and spatial scales: BMP gradients as short as 1-2 cell diameters maintain the stem cell niche of the Drosophila germarium over a 24-h cycle, and BMP gradients of several hundred microns establish dorsal-ventral tissue specification in Drosophila, zebrafish and Xenopus embryos in timescales between 30 min and several hours. The mechanisms that shape BMP signaling gradients are also incredibly diverse. Although ligand diffusion plays a dominant role in forming the gradient, a cast of diffusible and non-diffusible regulators modulate gradient formation and confer robustness, including scale invariance and adaptability to perturbations in gene expression and growth. In this Review, we document the diverse ways that BMP gradients are formed and refined, and we identify the core principles that they share to achieve reliable performance.

scholarly journals The Wnt pathway limits BMP signaling outside of the germline stem cell niche in Drosophila ovaries

2016 ◽  
Vol 417 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Violaine I. Mottier-Pavie ◽  
Victor Palacios ◽  
Susan Eliazer ◽  
Shane Scoggin ◽  
Michael Buszczak
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Wnt Pathway ◽  
Bmp Signaling ◽  
Germline Stem Cell ◽  
Cell Niche ◽  
Germline Stem Cell Niche

scholarly journals A PINCH-1–Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation

2019 ◽  
Vol 218 (11) ◽  
pp. 3773-3794
Author(s):  
Ling Guo ◽  
Rong Wang ◽  
Kuo Zhang ◽  
Jifan Yuan ◽  
Jiaxin Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Bmp Signaling ◽  
Signaling Mechanism ◽  
Ubiquitin Protein Ligase ◽  
Signaling Mechanisms ◽  
Morphogenetic Protein ◽  
Signaling Axis ◽  
Fate Decision

Mechano-environment plays multiple critical roles in the control of mesenchymal stem cell (MSC) fate decision, but the underlying signaling mechanisms remain undefined. We report here a signaling axis consisting of PINCH-1, SMAD specific E3 ubiquitin protein ligase 1 (Smurf1), and bone morphogenetic protein type 2 receptor (BMPR2) that links mechano-environment to MSC fate decision. PINCH-1 interacts with Smurf1, which inhibits the latter from interacting with BMPR2 and consequently suppresses BMPR2 degradation, resulting in augmented BMP signaling and MSC osteogenic differentiation (OD). Extracellular matrix (ECM) stiffening increases PINCH-1 level and consequently activates this signaling axis. Depletion of PINCH-1 blocks stiff ECM-induced BMP signaling and OD, whereas overexpression of PINCH-1 overrides signals from soft ECM and promotes OD. Finally, perturbation of either Smurf1 or BMPR2 expression is sufficient to block the effects of PINCH-1 on BMP signaling and MSC fate decision. Our findings delineate a key signaling mechanism through which mechano-environment controls BMPR2 level and MSC fate decision.

scholarly journals A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Brice Brookshire ◽  
Vicki Rosen
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Human Organ ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Bmp Pathway ◽  
Wide Perspective ◽  
The Relationship

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-βfamily of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-βpathways.

Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity

2008 ◽  
Vol 294 (6) ◽  
pp. C1387-C1397 ◽  
Author(s):  
Shaukat A. Khan ◽  
Matthew S. Nelson ◽  
Chendong Pan ◽  
Patrick M. Gaffney ◽  
Pankaj Gupta
Keyword(s):  
Heparan Sulfate ◽  
Bone Morphogenetic Proteins ◽  
Bone Development ◽  
Structural Features ◽  
Bmp Signaling ◽  
Hurler Syndrome ◽  
Multipotent Stem Cells ◽  
Pharmacological Agents ◽  
Chemically Modified ◽  
Morphogenetic Protein

Bone morphogenetic proteins (BMPs) and their endogenous antagonists are important for brain and bone development and tumor initiation and progression. Heparan sulfate (HS) proteoglycans (HSPG) modulate the activities of BMPs and their antagonists. How glycosaminoglycans (GAGs) influence BMP activity in various malignancies and in inherited abnormalities of GAG metabolism, and the structural features of GAGs essential for modulation of BMP signaling, remain incompletely defined. We examined whether chemically modified soluble heparins, the endogenous HS in malignant cells and the HS accumulated in Hurler syndrome cells influence BMP-4 signaling and activity. We show that both exogenous (soluble) and endogenous GAGs modulate BMP-4 signaling and activity, and that this effect is dependent on specific sulfate residues of GAGs. Our studies suggest that endogenous sulfated GAGs promote the proliferation and impair differentiation of malignant human cells, providing the rationale for investigating whether pharmacological agents that inhibit GAG synthesis or function might reverse this effect. Our demonstration of impairment of BMP-4 signaling by GAGs in multipotent stem cells in human Hurler syndrome identifies a mechanism that might contribute to the progressive neurological and skeletal abnormalities in Hurler syndrome and related mucopolysaccharidoses.

scholarly journals Intestinal epithelium-derived BMP controls stem cell self-renewal in Drosophila adult midgut

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Aiguo Tian ◽  
Jin Jiang
Keyword(s):  
Stem Cell ◽  
Intestinal Epithelium ◽  
Stem Cell Niche ◽  
Daughter Cell ◽  
Cell Number ◽  
Bmp Signaling ◽  
Self Renewal ◽  
Type Iv ◽  
Signal Production ◽  
Cell Niche

Stem cells are maintained in a specialized microenvironment called niche but the nature of stem cell niche remains poorly defined in many systems. Here we demonstrate that intestinal epithelium-derived BMP serves as a niche signal for intestinal stem cell (ISC) self-renewal in Drosophila adult midgut. We find that BMP signaling is asymmetric between ISC and its differentiated daughter cell. Two BMP ligands, Dpp and Gbb, are produced by enterocytes and act in conjunction to promote ISC self-renewal by antagonizing Notch signaling. Furthermore, the basement membrane-associated type IV collagens regulate ISC self-renewal by confining higher BMP signaling to ISCs. The employment of gut epithelia as a niche for stem cell self-renewal may provide a mechanism for direct communication between the niche and the environment, allowing niche signal production and stem cell number to be fine-tuned in response to various physiological and pathological stimuli.

scholarly journals Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads

2003 ◽  
Vol 14 (7) ◽  
pp. 2809-2817 ◽  
Author(s):  
Gyo Murakami ◽  
Tetsuro Watabe ◽  
Kunio Takaoka ◽  
Kohei Miyazono ◽  
Takeshi Imamura
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Type I ◽  
Protein Signaling ◽  
Reporter Construct ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein

Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-β type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.

scholarly journals Injury-stimulated and self-restrained BMP signaling dynamically regulates stem cell pool size during Drosophila midgut regeneration

2017 ◽  
Vol 114 (13) ◽  
pp. E2699-E2708 ◽  
Author(s):  
Aiguo Tian ◽  
Bing Wang ◽  
Jin Jiang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Population Size ◽  
Underlying Mechanism ◽  
Cell Number ◽  
Bmp Signaling ◽  
Pool Size ◽  
Lineage Differentiation ◽  
Morphogenetic Protein ◽  
Resident Stem Cells

Many adult organs rely on resident stem cells to maintain homeostasis. Upon injury, stem cells increase proliferation, followed by lineage differentiation to replenish damaged cells. Whether stem cells also change division mode to transiently increase their population size as part of a regenerative program and, if so, what the underlying mechanism is have remained largely unexplored. Here we show that injury stimulates the production of two bone morphogenetic protein (BMP) ligands, Dpp and Gbb, which drive an expansion of intestinal stem cells (ISCs) by promoting their symmetric self-renewing division in Drosophila adult midgut. We find that BMP production in enterocytes is inhibited by BMP signaling itself, and that BMP autoinhibition is required for resetting ISC pool size to the homeostatic level after tissue repair. Our study suggests that dynamic BMP signaling controls ISC population size during midgut regeneration and reveals mechanisms that precisely control stem cell number in response to tissue needs.

scholarly journals Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Boris Guyot ◽  
Sylvain Lefort ◽  
Thibault Voeltzel ◽  
Eve-Isabelle Pécheur ◽  
Véronique Maguer-Satta
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Fate ◽  
Bone Morphogenetic Proteins ◽  
Myeloid Leukemia ◽  
Cell Transformation ◽  
Bmp Signaling ◽  
Tumor Escape ◽  
Breast Cancers

Understanding mechanisms of cancer development is mandatory for disease prevention and management. In healthy tissue, the microenvironment or niche governs stem cell fate by regulating the availability of soluble molecules, cell-cell contacts, cell-matrix interactions, and physical constraints. Gaining insight into the biology of the stem cell microenvironment is of utmost importance, since it plays a role at all stages of tumorigenesis, from (stem) cell transformation to tumor escape. In this context, BMPs (Bone Morphogenetic Proteins), are key mediators of stem cell regulation in both embryonic and adult organs such as hematopoietic, neural and epithelial tissues. BMPs directly regulate the niche and stem cells residing within. Among them, BMP2 and BMP4 emerged as master regulators of normal and tumorigenic processes. Recently, a number of studies unraveled important mechanisms that sustain cell transformation related to dysregulations of the BMP pathway in stem cells and their niche (including exposure to pollutants such as bisphenols). Furthermore, a direct link between BMP2/BMP4 binding to BMP type 1 receptors and the emergence and expansion of cancer stem cells was unveiled. In addition, a chronic exposure of normal stem cells to abnormal BMP signals contributes to the emergence of cancer stem cells, or to disease progression independently of the initial transforming event. In this review, we will illustrate how the regulation of stem cells and their microenvironment becomes dysfunctional in cancer via the hijacking of BMP signaling with main examples in myeloid leukemia and breast cancers.

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