axon guidance molecule
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eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Sonia Taïb ◽  
Noël Lamandé ◽  
Sabrina Martin ◽  
Fanny Coulpier ◽  
Piotr Topilko ◽  
...  

Peripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found, in mice, that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels via the endothelial receptor UNC5B during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during postnatal period.


2021 ◽  
Author(s):  
Thanh T Le ◽  
Samantha L Payne ◽  
Maia N Buckwald ◽  
Lily A Hayes ◽  
Christopher B Burge ◽  
...  

AbstractIn breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Coinjection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrate that the axon guidance molecule Plexin B3 mediates cancer cell adhesion to and migration on sensory nerves. Together, our results identify a novel mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.SignificanceThe presence of nerves in breast tumors has been associated with poor outcome. Understanding the mechanisms by which nerves contribute to tumor progression could help identify novel strategies to target metastatic disease.


Cell Reports ◽  
2021 ◽  
Vol 37 (3) ◽  
pp. 109828
Author(s):  
Heike Blockus ◽  
Sebi V. Rolotti ◽  
Miklos Szoboszlay ◽  
Eugénie Peze-Heidsieck ◽  
Tiffany Ming ◽  
...  

2021 ◽  
Author(s):  
Aline Gonçalves Lio Copola ◽  
Íria Gabriela Dias dos Santos ◽  
Luiz Lehmann Coutinho ◽  
Luiz Eduardo Vieira Del Bem ◽  
Paulo Henrique de Almeida Campos Junior ◽  
...  

Abstract Background: The repulsive guidance molecule a (RGMa) is a GPI-anchor axon guidance molecule first found to play important roles during neuronal development. RGMa expression patterns and signalling pathways via Neogenin and/or as BMP coreceptors indicated that this axon guidance molecule could also be working in other processes and diseases, including during myogenesis. Previous works have consistently shown that RGMa is expressed in skeletal muscle cells and that its overexpression induces both nuclei accretion and hypertrophy in muscle cell lineages. However, the cellular components and molecular mechanisms induced by RGMa during the differentiation of skeletal muscle cells are poorly understood. In this work, the global transcription expression profile of RGMa-treated C2C12 myoblasts during the differentiation stage, obtained by RNA-seq, were reported. Results: RGMa treatment could modulate the expression pattern of 2,195 transcripts in C2C12 skeletal muscle, with 943 upregulated and 1,252 downregulated. Among them, RGMa interfered with the expression of several RNA types, including categories related to the regulation of RNA splicing and degradation. The data also suggested that RGMa hyperplasia effects could be due to their capacity to induce the expression of transcripts related to cell-cell adhesion, while RGMa effects on muscle hypertrophy might be due to (i) the activation of the mTOR-Akt independent axis and (ii) the regulation of the expression of transcripts related to atrophy. Finally, RGMa induced the expression of transcripts that encode skeletal muscle structural proteins and members of the signalling pathways associated with GEF and Rho/Rac, common secondary signals of skeletal muscle hypertrophy, and the canonical pathway of the RGMa/Neogenin signalling. Conclusions: These results provide comprehensive knowledge of skeletal muscle transcript changes and pathways in response to RGMa.


2020 ◽  
Author(s):  
Sonia Taïb ◽  
Noël Lamandé ◽  
Sabrina Martin ◽  
Piotr Topilko ◽  
Isabelle Brunet

AbstractPeripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during postnatal period.


2020 ◽  
Author(s):  
Hai Thanh Pham ◽  
Satoru Kondo ◽  
Kazuhira Endo ◽  
Naohiro Wakisaka ◽  
Yoshitaka Aoki ◽  
...  

Abstract Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features and neoangiogenesis and its prognostic significance for oropharyngeal cancer (OPC) patients. Thirty-two OPC patients who underwent biopsy and 17 normal patients who underwent tonsillectomy were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with normal tonsil tissues (p = 0.005). SEMA3A expression was negatively correlated with CD34 expression, which suggested that a higher microvascular density corresponded to a lower expression of SEMA3A (r = -0.466, p = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of human papillomavirus (HPV) status (p = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival and is associated with antiangiogenesis in OPC.


2019 ◽  
Author(s):  
Heike Blockus ◽  
Sebastian V. Rolotti ◽  
Miklos Szoboszlay ◽  
Tiffany Ming ◽  
Anna Schroeder ◽  
...  

The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via its Ig4-5 domains. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.


2018 ◽  
Vol 20 (1) ◽  
pp. 124 ◽  
Author(s):  
Apoorva Iyer ◽  
Svetlana Chapoval

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function, instructing a fine tuning of the immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal, and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro- or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 637-637 ◽  
Author(s):  
Simon Renders ◽  
Pia Sommerkamp ◽  
Jasper Panten ◽  
Luisa Ladel ◽  
Katharina Schönberger ◽  
...  

Abstract Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors that differentiate into lineage-committed progenitors and subsequently mature cells. Recently, we explored the molecular signatures employed by hematopoietic-stem-cells (HSCs) during differentiation by performing quantitative proteome, transcriptome (RNA-seq) and whole genome DNA methylation analyses on dormant and active HSCs as well as multipotent progenitors populations (MPP) 1-4 (Cabezas-Wallscheid et al., Cell 2017; Cabezas-Wallscheid et al., Cell Stem Cell 2014; Klimmeck et al., Stem Cell Reports 2014; Lipka et al., Cell Cycle 2014). By exploiting these datasets, we found the DCC-like cell surface receptor Neogenin (Neo) almost exclusively expressed in CD34negCD150+CD48negLSK HSCs with an even higher expression in dormant HSCs. In addition, Neo expression has been reported to be robustly upregulated in aged HSCs (Sun et al., Cell Stem Cell 2015). The Neogenin receptor can bind different neuronal guidance molecules and can function as a BMP co-receptor. Based on this, we hypothesized that Neo and its ligands may preserve HSC dormancy and function. To investigate its role, we analyzed HSCs isolated from Neogenin-mutant mice during homeostasis and in reconstitution assays after transplantation. Neogenin-mutant HSCs show initially a competitive repopulation advantage in chimeras compared to control cells, which was associated with reduced stem cell quiescence. In agreement, RNA-seq analysis of Neogenin-mutant HSCs revealed reduced expression of dormancy related factors including the Egr1 transcription factor encoded by the early growth response gene. In contrast to the initial phases, Neogenin-mutant mice presented reduced HSC numbers associated with massively reduced reconstitution potential in 15 months old aged chimeras, as well as a myeloid differentiation bias. Collectively, these data suggest a role for Neo in preserving HSC dormancy and preventing their premature ageing. With regard to ligands of the Neo receptor, only stimulation of cultured HSCs with the axon guidance molecule Netrin-1, but not with other known Neogenin ligands affected gene expression and cellular function of HSCs. This effect of Netrin-1 was absent in Neogenin-mutant HSC demonstrating specificity. In support of the hypothesis that Netrin-1- Neo signaling may preserve HSC function, treatment of cultured HSCs with Netrin-1 alone increased the reconstitution capabilities of HSCs after transplantation compared to untreated control cells. Taken together, our results identify the Neogenin receptor as a novel player important for promoting HSC maintenance through dormancy, while its inhibition leads to exhaustion and loss of HSC self-renewal capacity upon ageing. The here identified Netrin-1- Neo axis also raise the possibility that nerves growing into the bone marrow may control HSC dormancy and function by the production of the axon guidance molecule Netrin-1. Disclosures No relevant conflicts of interest to declare.


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