scholarly journals BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hanae Omiya ◽  
Shima Yamaguchi ◽  
Tomoyuki Watanabe ◽  
Takaaki Kuniya ◽  
Yujin Harada ◽  
...  
Keyword(s):  
Single Layer ◽  
Bmp Signaling ◽  
Mammalian Brain ◽  
Ependymal Cells ◽  
Early Postnatal Development ◽  
Radial Glial Cells ◽  
Bmp Receptor ◽  
Stage Of Development ◽  
Ependymal Differentiation ◽  
Receptor Inhibitor

AbstractThe lateral ventricles of the adult mammalian brain are lined by a single layer of multiciliated ependymal cells, which generate a flow of cerebrospinal fluid through directional beating of their cilia as well as regulate neurogenesis through interaction with adult neural stem cells. Ependymal cells are derived from a subset of embryonic neural stem-progenitor cells (NPCs, also known as radial glial cells) that becomes postmitotic during the late embryonic stage of development. Members of the Geminin family of transcriptional regulators including GemC1 and Mcidas play key roles in the differentiation of ependymal cells, but it remains largely unclear what extracellular signals regulate these factors and ependymal differentiation during embryonic and early-postnatal development. We now show that the levels of Smad1/5/8 phosphorylation and Id1/4 protein expression—both of which are downstream events of bone morphogenetic protein (BMP) signaling—decline in cells of the ventricular-subventricular zone in the mouse lateral ganglionic eminence in association with ependymal differentiation. Exposure of postnatal NPC cultures to BMP ligands or to a BMP receptor inhibitor suppressed and promoted the emergence of multiciliated ependymal cells, respectively. Moreover, treatment of embryonic NPC cultures with BMP ligands reduced the expression level of the ependymal marker Foxj1 and suppressed the emergence of ependymal-like cells. Finally, BMP ligands reduced the expression levels of Gemc1 and Mcidas in postnatal NPC cultures, whereas the BMP receptor inhibitor increased them. Our results thus implicate BMP signaling in suppression of ependymal differentiation from NPCs through regulation of Gemc1 and Mcidas expression during embryonic and early-postnatal stages of mouse telencephalic development.

scholarly journals Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce AIF-caspase independent cell death.

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Bmp Signaling ◽  
Lung Carcinomas ◽  
Bmp Receptor ◽  
Cell Death Pathway ◽  
Morphogenetic Protein ◽  
Receptor Inhibitor

Abstract Background: BMP is an evolutionary conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP inhibitor JL5 synergistically induces death of lung cancer cells.Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinomas (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC.Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. Ym155 mediated cell death is not caused by the inhibition of survivin but involves Ym155 binding to mitochondrial DNA leading to depletion of ATP. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus causing DNA double stranded breaks independent of caspase activation, which occurs only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus.Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionary conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight how to target AIF caspase-independent cell death using BMP inhibitors.

scholarly journals Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce Apoptosis-Inducing Factor (AIF) caspase independent cell death

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Bmp Signaling ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Evolutionarily Conserved ◽  
Apoptosis Inducing Factor ◽  
Receptor Inhibitor

Abstract Background: Bone morphogenetic protein (BMP) is an evolutionarily conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP receptor inhibitor JL5 synergistically induces death of lung cancer cells. Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinoma (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC cell lines. Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. This causes DNA double stranded breaks independent of caspase activation, which occur only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus. Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionarily conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight of how to target AIF caspase-independent cell death using BMP inhibitors.

scholarly journals Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce Apoptosis-Inducing Factor (AIF) caspase independent cell death

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Bmp Signaling ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Evolutionarily Conserved ◽  
Apoptosis Inducing Factor ◽  
Receptor Inhibitor

Abstract Background: Bone morphogenetic protein (BMP) is an evolutionarily conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP receptor inhibitor JL5 synergistically induces death of lung cancer cells.Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinoma (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC cell lines.Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. This causes DNA double stranded breaks independent of caspase activation, which occur only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus.Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionarily conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight of how to target AIF caspase-independent cell death using BMP inhibitors.

Cytological and Histological Study of Adult and Neonate Epidermis in Thick and Thin Skin of Various Anatomical Sites

2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Hydar Muhsin Khalfa ◽  
Adnan Albideri ◽  
Haider Salih Jaffat
Keyword(s):  
Histological Study ◽  
Single Layer ◽  
Sweat Glands ◽  
Anatomical Site ◽  
Basal Cells ◽  
Histological Changes ◽  
Mature Adult ◽  
Skin Development ◽  
Stage Of Development ◽  
Thin Skin

The integumentary system covers the surface of the embryo (skin) and its specialized skin structures including hair, nails, sweat glands, mammary glands and teeth. During fetal skin development, the epidermis changes from a single layer of ectodermal cells at 7–8 days of gestation into a more apparent stratified, keratinized epithelium at 22–24 weeks. The aim of the study is to identify the histological and cytological changes that take place during neonatal and adult epidermis development. Human neonatal and adult samples were obtained from fully informed, consenting parent or releatives from Al-hilla mortary / Iraq. Neonatal samples were obtained from neonates after sudden deaths from maternity wards. Anatomical Sites included abdomen, forehead, back, shoulder and feet sole. A totoal of 15 neonates and 10 mature adults were used for this study. Fresh tissues were sectioned using a freezing cryostat. Tissues were sectioned at 5µm in -24°C and collected on microscopic slides. Slides were allowed to air dry for 30 min prior to hematoxyline and eosin staining. Tissues were also photographed using scanning electron microscopy SEM. Cytological measurements were taken using image j software and data was analysed using graph prism. Various cytological and histological changes takes place during neonatal and adult and epidermis development. Our study shows the stages of fair follicule formation as well as number of nucleated layers present at each stage of development and at different anatomical sites. Major histological changes takes places during the transition frm a neonate to a mature adult including the number of basal cells and epidermal thickness depending on the anatomical site.

scholarly journals BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuya Morita ◽  
Naoyuki Matsumoto ◽  
Kengo Saito ◽  
Toshihide Hamabe-Horiike ◽  
Keishi Mizuguchi ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Molecular Mechanisms ◽  
Water Movement ◽  
Water Channel ◽  
Bmp Signaling ◽  
Aquaporin 4 ◽  
Mammalian Brain ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
Mouse Cerebral Cortex

AbstractAquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

scholarly journals Role of BMP receptor traffic in synaptic growth defects in an ALS model

2016 ◽  
Vol 27 (19) ◽  
pp. 2898-2910 ◽  
Author(s):  
Mugdha Deshpande ◽  
Zachary Feiger ◽  
Amanda K. Shilton ◽  
Christina C. Luo ◽  
Ethan Silverman ◽  
...  
Keyword(s):  
Neurological Impairment ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Synaptic Growth ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Bmp Receptor ◽  
Bmp Receptors ◽  
Induced Defects

TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment.

scholarly journals Xenopus gpx3 Mediates Posterior Development by Regulating Cell Death during Embryogenesis

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1265
Author(s):  
Hongchan Lee ◽  
Tayaba Ismail ◽  
Youni Kim ◽  
Shinhyeok Chae ◽  
Hong-Yeoul Ryu ◽  
...  
Keyword(s):  
Cell Death ◽  
Embryonic Development ◽  
Glutathione Peroxidase ◽  
Critical Role ◽  
Model Organism ◽  
Bmp Signaling ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Peroxidase Mimic ◽  
Tail Region ◽  
Stage Of Development

Glutathione peroxidase 3 (GPx3) belongs to the glutathione peroxidase family of selenoproteins and is a key antioxidant enzyme in multicellular organisms against oxidative damage. Downregulation of GPx3 affects tumor progression and metastasis and is associated with liver and heart disease. However, the physiological significance of GPx3 in vertebrate embryonic development remains poorly understood. The current study aimed to investigate the functional roles of gpx3 during embryogenesis. To this end, we determined gpx3’s spatiotemporal expression using Xenopus laevis as a model organism. Using reverse transcription polymerase chain reaction (RT-PCR), we demonstrated the zygotic nature of this gene. Interestingly, the expression of gpx3 enhanced during the tailbud stage of development, and whole mount in situ hybridization (WISH) analysis revealed gpx3 localization in prospective tail region of developing embryo. gpx3 knockdown using antisense morpholino oligonucleotides (MOs) resulted in short post-anal tails, and these malformed tails were significantly rescued by glutathione peroxidase mimic ebselen. The gene expression analysis indicated that gpx3 knockdown significantly altered the expression of genes associated with Wnt, Notch, and bone morphogenetic protein (BMP) signaling pathways involved in tailbud development. Moreover, RNA sequencing identified that gpx3 plays a role in regulation of cell death in the developing embryo. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone 3 (PH3) staining confirmed the association of gpx3 knockdown with increased cell death and decreased cell proliferation in tail region of developing embryos, establishing the involvement of gpx3 in tailbud development by regulating the cell death. Furthermore, these findings are inter-related with increased reactive oxygen species (ROS) levels in gpx3 knockdown embryos, as measured by using a redox-sensitive fluorescent probe HyPer. Taken together, our results suggest that gpx3 plays a critical role in posterior embryonic development by regulating cell death and proliferation during vertebrate embryogenesis.

scholarly journals Differential Timing and Coordination of Neurogenesis and Astrogenesis in Developing Mouse Hippocampal Subregions

2020 ◽  
Vol 10 (12) ◽  
pp. 909
Author(s):  
Allison M. Bond ◽  
Daniel A. Berg ◽  
Stephanie Lee ◽  
Alan S. Garcia-Epelboim ◽  
Vijay S. Adusumilli ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Postnatal Development ◽  
Fundamental Principle ◽  
Mammalian Brain ◽  
Early Postnatal Development ◽  
Neocortical Development ◽  
Mouse Hippocampus ◽  
Cornu Ammonis ◽  
Low Levels ◽  
Differential Timing

Neocortical development has been extensively studied and therefore is the basis of our understanding of mammalian brain development. One fundamental principle of neocortical development is that neurogenesis and gliogenesis are temporally segregated processes. However, it is unclear how neurogenesis and gliogenesis are coordinated in non-neocortical regions of the cerebral cortex, such as the hippocampus, also known as the archicortex. Here, we show that the timing of neurogenesis and astrogenesis in the Cornu Ammonis (CA) 1 and CA3 regions of mouse hippocampus mirrors that of the neocortex; neurogenesis occurs embryonically, followed by astrogenesis during early postnatal development. In contrast, we find that neurogenesis in the dentate gyrus begins embryonically but is a protracted process which peaks neonatally and continues at low levels postnatally. As a result, astrogenesis, which occurs during early postnatal development, overlaps with the process of neurogenesis in the dentate gyrus. During all stages, neurogenesis overwhelms astrogenesis in the dentate gyrus. In addition, we find that the timing of peak astrogenesis varies by hippocampal subregion. Together, our results show differential timing and coordination of neurogenesis and astrogenesis in developing mouse hippocampal subregions and suggest that neurogenesis and gliogenesis occur simultaneously during dentate gyrus development, challenging the conventional principle that neurogenesis and gliogenesis are temporally separated processes.

scholarly journals Scanning and Transmission Electron Microscopy of the Ependymal Lining of the Third Ventricle

1974 ◽  
Vol 1 (1) ◽  
pp. 59-73 ◽  
Author(s):  
J.E. Bruni
Keyword(s):  
Electron Microscope ◽  
Scanning Electron Microscope ◽  
Third Ventricle ◽  
Three Dimensional ◽  
Single Layer ◽  
Ependymal Cells ◽  
Ultrastructural Studies ◽  
The Third ◽  
Functional Involvement ◽  
Scanning Electron

SUMMARYIn its simplest form, the ependyma of the third ventricle consists of a single layer of cuboidal cells. Although these typical mural cells constitute the greater part of the lining of the ventricle, a specialized variety of ependymal cell (the tanycyte) can also be distinguished within circumscribed areas of the ventricular wall. Although such cells are found scattered throughout the dorsoventral extent of the third ventricle, they are particularly numerous along the ventrolateral walls and floor. The regional variation in the surface morphology of the ventricle walls as evident with the scanning electron microscope is consistent with this pattern of tanycyte distribution. Ultrastructural studies have established that the tanycyte is a fundamentally distinct cell with a long basal process extending into the subjacent neuropil and frequently directed toward a capillary wall. This unique morphology conforms closely to its three-dimensional appearance as demonstrated with the scanning electron microscope. The significance of ependymal tanycytes particularly of the third ventricle derives largely from the connections they establish between the ventricular lumen and vasculature of the median eminence. This intriguing structural relationship has led to the suggestion that ependymal cells and cerebrospinal fluid of the third ventricle may be involved in the regulation of adenohypophysial activity. Evidence indicating the functional involvement of specialized ependymal cells in the neuroendocrine control of pituitary activity is reviewed.

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