84,921 research outputs found

    The regulatory effect of semaphorin 7A on proliferation and migration in human umbilical vein endothelial cells

    Get PDF
    Semaphorin 7A (SEMA 7A), a factor originally identified as regulating axon growth, has recently been implicated as a pro-angiogenic factor. The molecular mechanisms for this ability to stimulate angiogenesis have not been identified. This study examines if SEMA 7A can have a direct effect on vascular endothelial cells or whether it indirectly induces angiogenesis through stimulation and recruitment of macrophages as has been suggested. Using human umbilical vein endothelial cells (HUVECs), the ability of SEMA 7A to affect proliferation and migration was examined. HUVECs were exposed to SEMA 7A directly or to conditioned media collected from macrophages exposed to SEMA 7A and a cell proliferation assay was performed. Additionally, the ability of the cells to migrate was also measured using a transwell and a scratch assay. Direct exposure of HUVECs to SEMA 7A resulted in a significant decrease in cell proliferation. Preliminary results also suggest that direct exposure also results in a slight inhibitory effect on the migration of HUVECs. SEMA 7A treatment of macrophages did not result in the production of factors that stimulate HUVECs to proliferate. Additionally, our results suggest that macrophages exhibited a slight stimulation of migration in response to SEMA 7A

    The Regulatory Effect of Semaphorin 7A on Proliferation and Migration in Human Umbilical Vein Endothelial Cells

    Get PDF
    Semaphorin 7A (SEMA 7A), a factor originally identified as regulating axon growth, has recently been implicated as a pro-angiogenic factor. The molecular mechanisms for this ability to stimulate angiogenesis have not been identified. This study examines if SEMA 7A can have a direct effect on vascular endothelial cells or whether it indirectly induces angiogenesis through stimulation and recruitment of macrophages as has been suggested. Using a human umbilical vein endothelial cells (HUVECs), the ability of SEMA 7A to affect proliferation and migration was examined. HUVECs were exposed to SEMA 7A directly or to conditioned media collected from macrophages exposed to SEMA 7A and a cell proliferation assay was performed. Additionally, the ability of the cells to migrate was also measured using a transwell and a scratch assay. Direct exposure of HUVECs to SEMA 7A resulted in a significant decrease in cell proliferation. Preliminary results also suggest that direct exposure also results in a slight inhibitory effect on the migration of HUVECs. SEMA 7A treatment of macrophages did not result in the production of factors that stimulate HUVECs to proliferate. Additionally, our results suggest that macrophages exhibited a slight stimulation of migration in response to SEMA 7A

    Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosis

    Get PDF
    Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli

    PlexinA1 Autoinhibition by the Plexin Sema Domain

    Get PDF
    AbstractSemaphorin 3A (Sema3A) binds to neuropilin-1 (NP1) and activates the transmembrane Plexin to transduce a repulsive axon guidance signal. Here, we show that Sema3 signals are transduced equally effectively by PlexinA1 or PlexinA2, but not by PlexinA3. Deletion analysis of the PlexinA1 ectodomain demonstrates that the sema domain prevents PlexinA1 activation in the basal state. Sema-deleted PlexinA1 is constitutively active, producing cell contraction, growth cone collapse, and inhibition of neurite outgrowth. The sema domain of PlexinA1 physically associates with the remainder of the PlexinA1 ectodomain and can reverse constitutive activation. Both the sema portion and the remainder of the ectodomain of PlexinA1 associate with NP1 in a Sema3A-independent fashion. Plexin A1 is autoinhibited by its sema domain, and Sema3A/NP1 releases this inhibition

    Sema-1a Reverse Signaling Promotes Midline Crossing In Response To Secreted Semaphorins

    Get PDF
    For the majority of axons, an essential step in proper guidance involves crossing the midline, and failure to do so often results in an inability to coordinate movement. Attraction to the midline depends in part on the highly conserved guidance receptor DCC, or Frazzled in Drosophila, which signals chemoattraction upon binding its ligand, Netrin. DCC mutations in humans are associated with mirror movement disorder, an inability to independently control the right and left sides of the body. Although Frazzled/Netrin signaling is required for many axons to cross the midline, netrin and frazzled/DCC mutants still exhibit significant midline crossing, implicating additional pro-crossing mechanisms. The Drosophila embryonic midline provides an ideal model to investigate nervous system development in vivo as it is genetically tractable and axon guidance cues are highly conserved. To identify additional pro-crossing pathways, we initiated a screen for modulators of midline crossing in a sensitized genetic background wherein Frazzled signaling is partially disrupted. Axon crossing defects in this background are enhanced by mutations in the transmembrane semaphorin, Sema-1a. Mutations in sema-1a also dominantly enhance crossing defects in a netrin mutant, indicating that Sema-1a functions in a Netrin independent pathway to promote midline crossing. Here we identify the transmembrane Semaphorin, Sema-1a, as a novel regulator of midline crossing in the Drosophila CNS. We show that Sema-1a functions as a receptor in response to the secreted Semaphorins, Sema-2a and Sema-2b, to promote midline crossing. In contrast to other examples of reverse signaling where Sema1a triggers repulsion through Plexin binding, in commissural neurons Sema-1a acts independently of Plexins to inhibit Rho and promote attraction to the midline. These findings suggest that Sema-1a reverse signaling can elicit distinct axonal responses depending on differential engagement of ligands and signaling effectors

    Neuropilin Is a Receptor for the Axonal Chemorepellent Semaphorin III

    Get PDF
    AbstractExtending axons in the developing nervous system are guided to their targets through the coordinate actions of attractive and repulsive guidance cues. The semaphorin family of guidance cues comprises several members that can function as diffusible axonal chemorepellents. To begin to elucidate the mechanisms that mediate the repulsive actions of Collapsin-1/Semaphorin III/D (Sema III), we searched for Sema III–binding proteins in embryonic rat sensory neurons by expression cloning. We report that Sema III binds with high affinity to the transmembrane protein neuropilin, and that antibodies to neuropilin block the ability of Sema III to repel sensory axons and to induce collapse of their growth cones. These results provide evidence that neuropilin is a receptor or a component of a receptor complex that mediates the effects of Sema III on these axons

    The Effect of Semaphorin 3A on Chick Embryo Retinal Growth Cones

    Get PDF
    During embryonic development, axons grow from the retina of the eye to the tectum of the brain which allows for visual information transfer. Axons travel to the tectum via axon pathfinding, which is influenced by axon guidance cues. Axon guidance molecules interact with the growing tips of retinal ganglion cell (RGC) axon, which are motile structures known as growth cones. Some inhibitory axon guidance molecules are known to cause a growth cone to collapse, where they cease growth and then retract, or turn away. One such inhibitory axon guidance molecule is Semaphorin 3A (Sema 3A). While Sema 3A’s importance is known in the nervous system, a study conducted by Luo et al. (1993) found that Sema 3A causes growth cone collapse of chick embryo dorsal root ganglion cells (DRGs) but not growth cone collapse in chick retinal ganglion cells (RGCs). However, we have found significant evidence that Sema 3A does indeed cause growth cone collapse of embryonic chick retinal ganglion cells, which is inconsistent with the Luo et al. (1993) finding. After further investigation, we have found that RGC’s have the ability to regenerate from collapse after a 15-20 minute treatment with Sema 3A, thus giving the illusion to Luo et at. (1993) that Sema 3A does not affect RGC’s because of the 60-minute allotted time window they used. We are currently investigating the effect of Sema 3A on different embryonic ages (E5, E6, E7, E8). We have found preliminary data that suggests that Sema 3A will give the same effect on RGC’s no matter the age.https://digitalcommons.winthrop.edu/sureposters/1012/thumbnail.jp

    Interlegality of Interfaith Marriages Vis a Vis Supreme Court Circular Letter Number 2 of 2023 on The Rejection of Applications for Registration of Interfaith Marriages in Indonesia

    Get PDF
    The polemic of interfaith marriages is not a new problem at the legal level in Indonesia, especially with the issuance of Supreme Court Circular Letter (SEMA) Number 2 of 2023 for District Courts to reject requests for registration of interfaith marriages. This has caused pros and cons in the community. The purpose of this research is to elaborate on the impact on the independence of judges and the constitutional rights of marriage actors, as well as the position of SEMA when faced with the rights of interfaith marriages conducted abroad and brought to Indonesia. This research can enrich insights into the discourse of interfaith marriage in Indonesia. This research uses a normative legal research method that relies on primary, secondary, and tertiary legal materials analyzed prescriptively. The results of this study are, First, SEMA can interfere with the independence of judicial power itself, where the Supreme Court is one of the actor of SEMA. Secondly, SEMA impacts the non-fulfillment of the constitutional rights of actors of interfaith marriages to obtain legal certainty, equality before the law, and legal protection. Thirdly, SEMA can trigger smuggling of law in interfaith marriages where the legal consequences must be recognized based on the principles of rights derived from foreign law, the principle of reciprocity, and the principle of comitas gentium. These three principles underlie the inter legality of interfaith marriages, so they have transnational legality. This research recommends that the Supreme Court revoke the SEMA that has been issued.The polemic of interfaith marriages is not a new problem at the legal level in Indonesia, especially with the issuance of Supreme Court Circular Letter (SEMA) Number 2 of 2023 for District Courts to reject requests for registration of interfaith marriages. This has caused pros and cons in the community. The purpose of this research is to elaborate on the impact on the independence of judges and the constitutional rights of marriage actors, as well as the position of SEMA when faced with the rights of interfaith marriages conducted abroad and brought to Indonesia. This research can enrich insights into the discourse of interfaith marriage in Indonesia. This research uses a normative legal research method that relies on primary, secondary, and tertiary legal materials analyzed prescriptively. The results of this study are, First, SEMA can interfere with the independence of judicial power itself, where the Supreme Court is one of the actor of SEMA. Secondly, SEMA impacts the non-fulfillment of the constitutional rights of actors of interfaith marriages to obtain legal certainty, equality before the law, and legal protection. Thirdly, SEMA can trigger smuggling of law in interfaith marriages where the legal consequences must be recognized based on the principles of rights derived from foreign law, the principle of reciprocity, and the principle of comitas gentium. These three principles underlie the inter legality of interfaith marriages, so they have transnational legality. This research recommends that the Supreme Court revoke the SEMA that has been issued
    • …
    corecore