scholarly journals Targeted Knockdown of Bone Morphogenetic Protein Signaling within Neural Progenitors Protects the Brain and Improves Motor Function following Postnatal Hypoxia-Ischemia

2018 ◽  
Vol 40 (1) ◽  
pp. 23-38 ◽  
Author(s):  
Robert W. Dettman ◽  
Derin Birch ◽  
Augusta Fernando ◽  
John A. Kessler ◽  
Maria L.V. Dizon
Keyword(s):  
Motor Function ◽  
Neural Progenitor Cells ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Artery Ligation ◽  
Newborn Brain ◽  
Carotid Artery Ligation ◽  
Conditional Deletion ◽  
Morphogenetic Protein ◽  
The Brain

Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss. Here, we showed that BMP signaling is upregulated within oligodendroglia of the neonatal brain. We tested the hypothesis that inhibition of BMP signaling specifically within neural progenitor cells (NPCs) is sufficient to protect oligodendroglia. We conditionally deleted the BMP receptor 2 subtype (BMPR2) in NG2-expressing cells after HI. We found that BMPR2 deletion globally protects the brain as assessed by MRI and protects motor function as assessed by digital gait analysis, and that conditional deletion of BMPR2 maintains oligodendrocyte marker expression by immunofluorescence and Western blot and prevents loss of oligodendroglia. Finally, BMPR2 deletion after HI results in an increase in noncompacted myelin. Thus, our data indicate that inhibition of BMP signaling specifically in NPCs may be a tractable strategy to protect the newborn brain from HI.

Effect of Tumor Growth Factor-β on Osteogenesis in Osteoporosis Rats by Regulating Bone Morphogenetic Protein Signaling Pathway

2020 ◽  
Vol 10 (12) ◽  
pp. 1884-1890
Author(s):  
Jing Tian ◽  
Qianying Zhao ◽  
Dapeng Zhou ◽  
Bing Xie
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Control Group ◽  
Protein Signaling ◽  
Alp Activity ◽  
Tissue Repair And Regeneration ◽  
Tumor Growth Factor ◽  
Morphogenetic Protein ◽  
Proliferation And Differentiation

The balance of osteoblasts and osteoclasts is critical for bone formation and remodeling and imbalance causes osteoporosis (OP). TGF-β regulates bone tissue repair and regeneration, but TGF-β’s role in osteogenesis in OP has not been elucidated. OVX-induced OP rat models were constructed and rat BMSCs were isolated and assigned into control group, OP group, and TGF-β group (transfected with TGF-β1 plasmid followed by analysis of cell proliferation by MTT assay, RUNX2 and OPN expression by Real time PCR, ALP activity and secretion of TGF-β, BMP-2 and BMP-9 by ELISA. In addition, RANKL was added to induce BMSCs differentiation into to osteoclasts which were transfected with TGF-β1 followed by analysis of cell proliferation, c-Fos and TRAP expression and secretion of BMP-2 and BMP-9. OP group rats had significantly reduced secretion of TGF-β1, BMP-2 and BMP-9, reduced cell proliferation, decreased RUNX2 and OPN expression and ALP activity (P <0.05). Transfection of TGF-β1 in BMSCs of OP group rats could significantly reverse the above changes (P <0.05). TGF-β1 significantly inhibited osteoclast proliferation, decreased expression of c-Fos and TRAP, and increased secretion of BMP-2 and BMP-9 (P <0.05). TGF-β1 level in OP is decreased. Up-regulating TGF-β promotes osteoblast differentiation in OP rats by regulating BMP signaling pathway, and inhibits osteoclast proliferation and differentiation.

scholarly journals Bone Morphogenetic Protein Signaling Restricts Proximodistal Extension of the Ventral Fin Fold

2020 ◽  
Vol 8 ◽  
Author(s):  
Jun Ka ◽  
Jun-Dae Kim ◽  
Boryeong Pak ◽  
Orjin Han ◽  
Woosoung Choi ◽  
...  
Keyword(s):  
Cell Division ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Distal Migration ◽  
Cellular Behaviors ◽  
And Shifts ◽  
Migration Of Cells

Unpaired fins, which are the most ancient form of locomotory appendages in chordates, had emerged at least 500 million years ago. While it has been suggested that unpaired fins and paired fins share structural similarities, cellular and molecular mechanisms that regulate the outgrowth of the former have not been fully elucidated yet. Using the ventral fin fold in zebrafish as a model, here, we investigate how the outgrowth of the unpaired fin is modulated. We show that Bone Morphogenetic Protein (BMP) signaling restricts extension of the ventral fin fold along the proximodistal axis by modulating diverse aspects of cellular behaviors. We find that lack of BMP signaling, either caused by genetic or chemical manipulation, prolongs the proliferative capacity of epithelial cells and substantially increases the number of cells within the ventral fin fold. In addition, inhibition of BMP signaling attenuates the innate propensity of cell division along the anteroposterior axis and shifts the orientation of cell division toward the proximodistal axis. Moreover, abrogating BMP signaling appears to induce excessive distal migration of cells within the ventral fin fold, and therefore precipitates extension along the proximodistal axis. Taken together, our data suggest that BMP signaling restricts the outgrowth of the ventral fin fold during zebrafish development.

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.

scholarly journals Membrane targeting of inhibitory Smads through palmitoylation controls TGF-β/BMP signaling

2017 ◽  
Vol 114 (50) ◽  
pp. 13206-13211 ◽  
Author(s):  
Wenqing Li ◽  
Weini Li ◽  
Lihui Zou ◽  
Shanming Ji ◽  
Chaoyi Li ◽  
...  
Keyword(s):  
Cellular Membrane ◽  
Bmp Signaling ◽  
Tissue Homeostasis ◽  
Membrane Association ◽  
Type I ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Stem Cell Regulation ◽  
Morphogenetic Protein ◽  
Signaling Activity

TGF-β/BMP (bone morphogenetic protein) signaling pathways play conserved roles in controlling embryonic development, tissue homeostasis, and stem cell regulation. Inhibitory Smads (I-Smads) have been shown to negatively regulate TGF-β/BMP signaling by primarily targeting the type I receptors for ubiquitination and turnover. However, little is known about how I-Smads access the membrane to execute their functions. Here we show that Dad, the Drosophila I-Smad, associates with the cellular membrane via palmitoylation, thereby targeting the BMP type I receptor for ubiquitination. By performing systematic biochemistry assays, we characterized the specific cysteine (Cys556) essential for Dad palmitoylation and membrane association. Moreover, we demonstrate that dHIP14, a Drosophila palmitoyl acyl-transferase, catalyzes Dad palmitoylation, thereby inhibiting efficient BMP signaling. Thus, our findings uncover a modification of the inhibitory Smads that controls TGF-β/BMP signaling activity.

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 IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes

2004 ◽  
Vol 164 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Jenny Hsieh ◽  
James B. Aimone ◽  
Brian K. Kaspar ◽  
Tomoko Kuwabara ◽  
Kinichi Nakashima ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Single Molecule ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Protein Signaling ◽  
Adult Rat ◽  
Morphogenetic Protein ◽  
Modeling Analysis ◽  
Igf I

Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

scholarly journals Surge of Corticocardiac Coupling in SHRSP Rats Exposed to Forebrain Cerebral Ischemia

2018 ◽  
Author(s):  
Fangyun Tian ◽  
Tiecheng Liu ◽  
Gang Xu ◽  
Talha Ghazi ◽  
Azeem Sajjad ◽  
...  
Keyword(s):  
Sudden Death ◽  
Cardiac Response ◽  
Artery Ligation ◽  
Spontaneously Hypertensive ◽  
Ecg Signals ◽  
Wky Rats ◽  
Carotid Artery Ligation ◽  
Bilateral Common Carotid Artery ◽  
Wistar Kyoto ◽  
The Brain

AbstractSudden death is an important but under-recognized consequence of stroke. Acute stroke can disturb central control of autonomic function, and result in cardiac dysfunction and sudden death. Previous study showed that bilateral common carotid artery ligation (BCCAL) in spontaneously hypertensive stroke-prone rats (SHRSP) is a well-established model for forebrain ischemic sudden death. This study aims to investigate the temporal dynamic changes in electrical activities of the brain and heart and functional interactions between the two vital organs following forebrain ischemia. EEG and ECG signals were simultaneously collected from 9 SHRSP and 8 Wistar-Kyoto (WKY) rats. RR interval and cardiac arrhythmias were analyzed to investigate the cardiac response to brain ischemia. EEG power and coherence (CCoh) analysis were conducted to study the cortical response. Corticocardiac coherence (CCCoh) and directional connectivity (CCCon) were analyzed to determine brain-heart connection. Heart rate variability (HRV) was analyzed to evaluate autonomic functionality. BCCAL resulted in 100% mortality in SHRSP within 14 hours, whereas no mortality was observed in WKY. The functionality of both the brain and the heart were significantly altered in SHRSP compared to WKY after BCCAL. SHRSP rats, but not WKY rats, exhibited intermittent surge of CCCoh, which paralleled the elevated CCCon and reduced HRV, following the onset of ischemia until sudden death. Elevated brain-heart coupling invariably associated with the disruption of the autonomic nervous system and the risk of sudden death. This study may improve our understanding of the mechanism of ischemic stroke-induced sudden death.

scholarly journals Scale invariance of BMP signaling gradients in zebrafish

2018 ◽  
Author(s):  
Yan Huang ◽  
David Umulis
Keyword(s):  
Scale Invariance ◽  
Bmp Signaling ◽  
Spatial Patterning ◽  
Protein Signaling ◽  
Wild Type ◽  
Bone Morphogenetic Protein Signaling ◽  
Cross Sectional ◽  
Morphogenetic Protein ◽  
Core Questions ◽  
Gradient Scaling

In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.

Abstract WMP116: The Effects of Immediate Treatment with Inter-alpha Inhibitor Proteins on Apoptosis in Neonatal Rats Exposed to Hypoxic-ischemic Injury

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sakura Nakada ◽  
Xiaodi Chen ◽  
Yow-Pin Lim ◽  
Barbara S Stonestreet
Keyword(s):  
Sham Group ◽  
Systemic Treatment ◽  
Male Rats ◽  
Neonatal Rats ◽  
Artery Ligation ◽  
Neuroprotective Effects ◽  
Group Assignment ◽  
Carotid Artery Ligation ◽  
Cellular Markers ◽  
The Brain

Background: Hypoxia-Ischemia (HI) is a condition in which the brain is deprived of adequate blood and oxygen supplies, resulting in a variety of neurodevelopmental morbidities in newborns. Inter-Alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins that have anti-inflammatory properties in systemic inflammatory disorders. The neuroprotective effects of treatment with IAIPs on apoptosis resulting from HI-related injury have not been examined yet. Objective: To investigate the effects of systemic treatment with IAIPs on apoptosis in HI-exposed neonatal rats. Design/Methods: Postnatal day 7 rats were randomly assigned to one of three groups: Placebo-Sham (PL-Sham, n=8), Placebo-HI (PL-HI, n=8) and IAIP-HI (n=8) groups. The PL-Sham group was not exposed to HI and received placebo intraperitoneally (0.9% NaCl); the PL-HI group was exposed to HI and received placebo (0.9% NaCl); the IAIP-HI group was exposed to HI and received IAIPs treatment (30 mg/kg). The Rice-Vannucci model was utilized to induce HI-related brain injury: unilateral carotid artery ligation followed by hypoxia (90 min in 8% O 2 ). Rat sex was recorded. Placebo or IAIP treatment was given at 0, 24 and 48 hours after HI, and brains were perfused and fixed at 72 hours. Fixed brain tissues were immunohistochemically stained with TUNEL apoptotic cellular markers. Apoptotic cells were counted without knowledge of the group assignment using the StereoInvestigator 10.0, Fractionator probe (MBF Bioscience). Results: There were more TUNEL positive cells in the PL-HI group than in the PL-Sham group overall (female+male) as well as in males in the cortex, total hemisphere and hippocampus (all P <0.05), but not in females ( P =0.11, P =0.30 and P =0.12, respectively). There appeared to be less apoptosis in the male IAIP-treated HI rats compared with the male placebo-treated HI rats ( P =0.29 for hemisphere and cortex, P =0.51 for hippocampus). Conclusion: Apoptosis is significantly increased after HI in the total hemisphere, cortex, and hippocampus of male neonatal rats, but not in females. Further investigation is needed to determine the neuroprotective effects of IAIPs on apoptosis in HI-exposed neonatal rats, although preliminary data suggests a protective trend for male rats.

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