RESUMO
Sympathetic nerves innervate most organs and regulate organ blood flow. Specifically, in the uterus, estradiol (E2) elicits rapid degeneration of sympathetic axons and stimulates the growth of blood vessels. Both physiological remodeling processes, critical for reproduction, have been extensively studied but as independent events and are still not fully understood. Here, we examine the neuropilin-1 (NRP1), a shared receptor for axon guidance and angiogenic factors. Systemic estradiol or vehicle were chronically injected to prepubertal rats and uterine and sympathetic chain sections immunostained for NRP1. Uterine semaphorin-3A mRNA was evaluated by in situ hybridization. Control sympathetic uterine-projecting neurons (1-month-old) expressed NRP1 in their somas but not in their intrauterine terminal axons. Estradiol did not affect NRP1 in the distal ganglia. However, at the entrance of the organ, some sympathetic NRP1-positive nerves were recognized. Vascular NRP1 was confined to intrauterine small-diameter vessels in both hormonal conditions. Although the overall pattern of NRP1-IR was not affected by E2 treatment, a subpopulation of infiltrated eosinophil leukocytes showed immunoreactivity for NRP1. Sema3A transcripts were detected in this cellular type as well. No NRP1-immunoreactive axons nor infiltrated eosinophils were visualized in other estrogenized pelvic organs. Together, these data suggest the involvement of NRP1/Sema3A signaling in the selective E2-induced uterine neurovascular remodeling. Our data support a model whereby NRP1 could coordinate E2-induced uterine neurovascular remodeling, acting as a positive regulator of growth when expressed in vessels and as a negative regulator of growth when expressed on axons.
Assuntos
Plasticidade Neuronal , Neuropilina-1/fisiologia , Semaforina-3A/fisiologia , Sistema Nervoso Simpático , Útero , Remodelação Vascular , Animais , Estradiol/farmacologia , Feminino , Ratos , Ratos Wistar , Útero/irrigação sanguínea , Útero/inervaçãoRESUMO
When spinal cord injury (SCI) occurs, a great number of inhibitors of axonal regeneration consecutively invade the injured site. The first protein to reach the lesion is known as semaphorin 3A (Sema3A), which serves as a powerful inhibitor of axonal regeneration. Mechanistically binding of Sem3A to the neuronal receptor complex neuropilin-1 (NRP-1) / PlexinA4 prevents axonal regeneration. In this special article we review the effects of galectin-1 (Gal-1), an endogenous glycan-binding protein, abundantly present at inflammation and injury sites. Notably, Gal1 adheres selectively to the NRP-1/PlexinA4 receptor complex in injured neurons through glycan-dependent mechanisms, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. While both the monomeric and dimeric forms of Gal-1 contribute to "switch-off" classically-activated microglia, only dimeric Gal-1 binds to the NRP-1/PlexinA4 receptor complex and promotes axonal regeneration. Thus, dimeric Gal-1 promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A adhering to the NRP-1/PlexinA4 complex, supporting the use of dimeric Gal-1 for the treatment of SCI patients.
Assuntos
Axônios/fisiologia , Galectina 1/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Humanos , Camundongos , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-1/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforina-3A/fisiologiaRESUMO
Intrathymic T cell differentiation takes place within the thymic lobules and depends on interactions between developing thymocytes and cells of the thymic microenvironment. Along with differentiation, thymocytes migrate in an oriented progression, which is tightly regulated by a number of interactions, including one mediated by the chemokine CXCL12. It has been shown recently that SEMA-3A, a soluble member of the semaphorin family, is also involved in this human thymocyte migration and can have a chemorepulsive and de-adhesive role. Herein, we study the role of SEMA-3A on the CXCL12-driven migration of human thymocytes. We have shown that SEMA-3A is able to inhibit the chemotaxis triggered by CXCL12. Such an inhibition was seen in respect to immature and mature CD4/CD8-defined thymocyte subsets and can be reverted specifically by neutralizing anti-SEMA-3A mAb. We have also shown that SEMA-3A consistently down-regulates CXCR4 membrane expression in all CD4/CD8-defined thymocyte subsets, and this down-regulation is accompanied by a decrease in the phosphorylation of FAK and ZAP-70 protein kinases. Taken together, these results demonstrate the involvement of SEMA-3A in the regulation of CXCL12-driven human thymocyte migration, where it acts as a physiological antagonist.
Assuntos
Axônios/fisiologia , Inibição de Migração Celular/imunologia , Quimiocina CXCL12/imunologia , Semaforina-3A/fisiologia , Subpopulações de Linfócitos T/imunologia , Timo/citologia , Anticorpos Neutralizantes/farmacologia , Quimiocina CXCL12/metabolismo , Quimiotaxia de Leucócito/imunologia , Pré-Escolar , Regulação para Baixo/imunologia , Humanos , Lactente , Recém-Nascido , Semaforina-3A/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismoRESUMO
By analyzing the mechanisms that govern dopaminergic axon pathfinding from the midbrain to the striatum in embryonic rat brains, we identified neuroepithelial regions that exert chemotropic effects on mesencephalic dopaminergic axons. Explants from the pretectum and the striatum showed an attractive effect, whereas those from the midhindbrain boundary, the dorsal thalamus, and the ventral thalamus had no effect. Expression of semaphorin (Sema) 3C and Sema3F in the pretectum and of Sema3A in the striatum suggested a role for these axon guidance molecules in dopaminergic axon pathfinding. When expressed in HEK293 cell aggregates, Sema3C had an attractive effect and enhanced axon growth, Sema3A enhanced axon growth, and Sema3F had a repulsive effect on dopaminergic axons. Antineuropilin-1 and antineuropilin-2 antibodies reduced attraction by the pretectum, whereas attraction by the striatum was not affected by the presence of antineuropilin-1 antibodies. Moreover, neuropilin-1- and neuropilin-2-soluble Fc chimeras reduced the attraction by the pretectum. These results suggest that semaphorins may help to establish the dopaminergic projection from the midbrain to the striatum during embryonic development.