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Journal of Molecular and Cellular... May 2021The intracardiac nervous system (ICNS) is composed of neurons, in association with Schwann cells (SC) and endoneurial cardiac fibroblasts (ECF). Besides heart rhythm...
BACKGROUND
The intracardiac nervous system (ICNS) is composed of neurons, in association with Schwann cells (SC) and endoneurial cardiac fibroblasts (ECF). Besides heart rhythm control, recent studies have implicated cardiac nerves in postnatal cardiac regeneration and cardiomyocyte size regulation, but cardiac SC and ECF remain understudied. During the postnatal period, the ICNS undergoes intense remodeling with nerve fasciculation and elongation throughout the myocardium, partially guided by the extracellular matrix (ECM). Here we report the origins, heterogeneity, and functions of SC and ECF that develop in proximity to neurons during postnatal ICNS maturation.
METHODS AND RESULTS
Periostin lineage (Postn+) cells include cardiac Remak SC and ECF during the postnatal period in mice. The developmental origins of cardiac SC and ECF were examined using Rosa26 reporter mice bred with Wnt1Cre, expressed in Neural crest (NC)-derived lineages, or tamoxifen-inducible Tcf21MerCreMer, expressed predominantly in epicardial-derived fibroblast lineages. ICNS components are NC-derived with the exceptions of the myelinating Plp1+ SC and the Tcf21+ lineage-derived intramural ventricular ECF. In addition, Postn+ lineage GFAP- Remak SC and ECF are present around the fasciculating cardiac nerves. Whole mount studies of the NC-derived cells confirmed postnatal maturation of the complex ICNS network from P0 to P30. Sympathetic, parasympathetic, and sensory neurons fasciculate from P0 to P7 indicated by co-staining with PSA-NCAM. Ablation of Postn+ cells from P0 to P6 or loss of Periostin leads to reduced fasciculation of cardiac sympathetic nerves. In addition, collagen remodeling surrounding maturing nerves of the postnatal heart is reduced in Postn-null mice.
CONCLUSIONS
Postn+ cells include cardiac SC and ECF during postnatal nerve maturation, and these cells have different embryonic origins. At P7, the Postn+ cells associated with cardiac nerves are mainly Remak SC and ECF. Ablation of the Postn+ cells from P0 to P6 and also loss of Postn in Postn-null mice leads to reduced fasciculation of cardiac nerves at P7.
Topics: Animals; Axon Fasciculation; Cell Adhesion Molecules; Fibroblasts; Gene Expression; Mice; Schwann Cells; Sympathetic Nervous System
PubMed: 33582160
DOI: 10.1016/j.yjmcc.2021.02.001 -
The European Journal of Neuroscience Feb 2022Previous studies show that the main cannabinoid receptor in the brain-cannabinoid type 1 receptor (CB1R)-is required for establishment of axonal projections in...
Previous studies show that the main cannabinoid receptor in the brain-cannabinoid type 1 receptor (CB1R)-is required for establishment of axonal projections in developing neurons but questions remain regarding the cellular and molecular mechanisms, especially in neurons developing in their native environment. We assessed the effects of CB1R signalling on growth cone filopodia and axonal projections of retinal ganglion cells (RGCs) in whole mount brains from Xenopus laevis tadpoles. Our results indicate that growth cones of RGC axons in brains from tadpoles exposed to a CB1R agonist had fewer filopodial protrusions, whereas growth cones from tadpoles exposed to a CB1R inverse agonist had more filopodia than growth cones of RGC axons in whole brains from control tadpoles. However, application of both the CB1R agonist and inverse agonist resulted in RGC axons that were overly dispersed and undulatory in the optic tract in situ. In addition, expression of a mutant for cadherin adhesive factor, β-catenin, that disrupts its binding to α-catenin, and application of an inhibitor for actin regulator non-muscle Myosin II, phenocopied the effects of the CB1R agonist and inverse agonist on growth cone filopodia, respectively. These findings suggest that both destablization and stabilization of growth cone filopodia are required for RGC axonal fasciculation/defasciculation in the optic tract and that CB1R regulates growth cone filopodia and axon dispersion of RGCs by oppositely modulating β-catenin adhesive and Myosin II actin regulatory functions. This study extends and confirms our understanding of cannabinoid mechanisms in sculpting developing neuronal circuits in vivo.
Topics: Actins; Animals; Axons; Cannabinoids; Growth Cones; Larva; Optic Tract; Pseudopodia; Receptors, Cannabinoid; Retinal Ganglion Cells; Xenopus laevis; beta Catenin
PubMed: 35060216
DOI: 10.1111/ejn.15603 -
Developmental Cell Jan 2019Neurite fasciculation through contact-dependent signaling is important for the wiring and function of the neuronal circuits. Here, we describe a type of axon-dendrite...
Neurite fasciculation through contact-dependent signaling is important for the wiring and function of the neuronal circuits. Here, we describe a type of axon-dendrite fasciculation in C. elegans, where proximal dendrites of the nociceptor PVD adhere to the axon of the ALA interneuron. This axon-dendrite fasciculation is mediated by a previously uncharacterized adhesive signaling by the ALA membrane signal SAX-7/L1CAM and the PVD receptor SAX-3/Robo but independent of Slit. L1CAM physically interacts with Robo and instructs dendrite adhesion in a Robo-dependent manner. Fasciculation mediated by L1CAM-Robo signaling aligns F-actin dynamics in the dendrite growth cone and facilitates dynamic growth cone behaviors for efficient dendrite guidance. Disruption of PVD dendrite fasciculation impairs nociceptive mechanosensation and rhythmicity in body curvature, suggesting that dendrite fasciculation governs the functions of mechanosensory circuits. Our work elucidates the molecular mechanisms by which adhesive axon-dendrite signaling shapes the construction and function of sensory neuronal circuits.
Topics: Actin Cytoskeleton; Actins; Animals; Axon Fasciculation; Axons; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cytoskeleton; Dendrites; Growth Cones; Nerve Tissue Proteins; Neural Cell Adhesion Molecule L1; Receptors, Immunologic; Roundabout Proteins
PubMed: 30555000
DOI: 10.1016/j.devcel.2018.10.028 -
Vertebrate spinal commissural neurons: a model system for studying axon guidance beyond the midline.Wiley Interdisciplinary Reviews.... 2015For bilaterally symmetric organisms, the transfer of information between the left and right side of the nervous system is mediated by commissures formed by neurons that... (Review)
Review
For bilaterally symmetric organisms, the transfer of information between the left and right side of the nervous system is mediated by commissures formed by neurons that project their axons across the body midline to the contralateral side of the central nervous system (CNS). After crossing the midline, many of these axons must travel long distances to reach their targets, including those that extend from spinal commissural neurons. Owing to the highly stereotyped trajectories of spinal commissural neurons that can be divided into several segments as these axons project to their targets, it is an ideal system for investigators to ask fundamental questions related to mechanisms of short- and long-range axon guidance, fasciculation, and choice point decisions at the midline intermediate target. In addition, studies of patterning genes of the nervous system have revealed complex transcription factor codes that function in a combinatorial fashion to specify individual classes of spinal neurons including commissural neurons. Despite these advances and the functional importance of spinal commissural neurons in mediating the transfer of external sensory information from the peripheral nervous system (PNS) to the CNS, only a handful of studies have begun to elucidate the mechanistic logic underlying their long-range pathfinding and the characterization of their synaptic targets. Using in vitro assays, in vivo labeling methodologies, in combination with both loss- and gain-of-function experiments, several studies have revealed that the molecular mechanisms of long-range spinal commissural axon pathfinding involve an interplay between classical axon guidance cues, morphogens and cell adhesion molecules. For further resources related to this article, please visit the WIREs website.
Topics: Animals; Axons; Cell Adhesion Molecules; Commissural Interneurons; Gene Expression Regulation, Developmental; Models, Neurological; Neurogenesis; Transcription Factors; Vertebrates
PubMed: 25619385
DOI: 10.1002/wdev.173 -
Developmental Biology Feb 2015Sensory trigeminal growth cones innervate the cornea in a coordinated fashion during embryonic development. Polysialic acid (polySia) is known for its important roles...
Sensory trigeminal growth cones innervate the cornea in a coordinated fashion during embryonic development. Polysialic acid (polySia) is known for its important roles during nerve development and regeneration. The purpose of this work is to determine whether polySia, present in developing eyefronts and on the surface of sensory nerves, may provide guidance cues to nerves during corneal innervation. Expression and localization of polySia in embryonic day (E)5-14 chick eyefronts and E9 trigeminal ganglia were identified using Western blotting and immunostaining. Effects of polySia removal on trigeminal nerve growth behavior were determined in vivo, using exogenous endoneuraminidase (endoN) treatments to remove polySia substrates during chick cornea development, and in vitro, using neuronal explant cultures. PolySia substrates, made by the physical adsorption of colominic acid to a surface coated with poly-d-lysine (PDL), were used as a model to investigate functions of the polySia expressed in axonal environments. PolySia was localized within developing eyefronts and on trigeminal sensory nerves. Distributions of PolySia in corneas and pericorneal regions are developmentally regulated. PolySia removal caused defasciculation of the limbal nerve trunk in vivo from E7 to E10. Removal of polySia on trigeminal neurites inhibited neurite outgrowth and caused axon defasciculation, but did not affect Neural Cell Adhesion Molecule (NCAM) expression or Schwann cell migration in vitro. PolySia substrates in vitro inhibited outgrowth of trigeminal neurites and promoted their fasciculation. In conclusion, polySia is localized on corneal nerves and in their targeting environment during early developing stages of chick embryos. PolySias promote fasciculation of trigeminal axons in vivo and in vitro, whereas, in contrast, their removal promotes defasciculation.
Topics: Animals; Axons; Cell Movement; Cell Survival; Chick Embryo; Cornea; Embryonic Development; Fasciculation; Laminin; Neural Cell Adhesion Molecules; Neurites; Schwann Cells; Sensation; Sialic Acids; Trigeminal Nerve
PubMed: 25478909
DOI: 10.1016/j.ydbio.2014.11.020 -
Frontiers in Neural Circuits 2021Precise positioning of neurons resulting from cell division and migration during development is critical for normal brain function. Disruption of neuronal migration can...
Precise positioning of neurons resulting from cell division and migration during development is critical for normal brain function. Disruption of neuronal migration can cause a myriad of neurological disorders. To investigate the functional consequences of defective neuronal positioning on circuit function, we studied a zebrafish () loss-of-function mutant () where the facial branchiomotor (FBM) neurons fail to migrate out of their birthplace. A jaw movement assay, which measures the opening of the zebrafish jaw (gape), showed that the frequency of gape events, but not their amplitude, was decreased in mutants. Consistent with this, a larval feeding assay revealed decreased food intake in mutants, indicating that the FBM circuit in mutants generates defective functional outputs. We tested various mechanisms that could generate defective functional outputs in mutants. While is ubiquitously expressed in neural and non-neural tissues, jaw cartilage and muscle developed normally in mutants, and muscle function also appeared to be unaffected. Although FBM neurons were mispositioned in mutants, axon pathfinding to jaw muscles was unaffected. Moreover, neuromuscular junctions established by FBM neurons on jaw muscles were similar between wildtype siblings and mutants. Interestingly, motor axons innervating the interhyoideus jaw muscle were frequently defasciculated in mutants. Furthermore, GCaMP imaging revealed that mutant FBM neurons were less active than their wildtype counterparts. These data show that aberrant positioning of FBM neurons in mutants is correlated with subtle defects in fasciculation and neuronal activity, potentially generating defective functional outputs.
Topics: Animals; Axons; Cell Movement; Motor Neurons; Neurogenesis; Zebrafish; Zebrafish Proteins
PubMed: 34248505
DOI: 10.3389/fncir.2021.690475 -
The Journal of Neuroscience : the... Mar 2015Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing...
Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye-brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues.
Topics: Animals; Axons; Female; Frizzled Receptors; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Retinal Ganglion Cells; Visual Pathways
PubMed: 25788689
DOI: 10.1523/JNEUROSCI.3304-13.2015 -
Cell Death & Disease Oct 2018The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK...
The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Mice deficient in Mkk4, Mkk7, and both Mkk4 and Mkk7 were generated. Immunohistochemistry was used to study the distribution and structure of retinal cell types and to assess RGC survival after optic nerve injury (mechanical controlled optic nerve crush (CONC)). Adult Mkk4- and Mkk7-deficient retinas had all retinal cell types, and with the exception of small areas of disrupted photoreceptor lamination in Mkk4-deficient mice, the retinas of both mutants were grossly normal. Deficiency of Mkk4 or Mkk7 reduced JNK signaling in RGCs after axonal injury and resulted in a significantly greater percentage of surviving RGCs 35 days after CONC as compared to wild-type controls (Mkk4: 51.5%, Mkk7: 29.1%, WT: 15.2%; p < 0.001). Combined deficiency of Mkk4 and Mkk7 caused failure of optic nerve formation, irregular retinal axonal trajectories, disruption of retinal lamination, clumping of RGC bodies, and dendritic fasciculation of dopaminergic amacrine cells. These results suggest that MKK4 and MKK7 may serve redundant and unique roles in molecular signaling important for retinal development and injury response following axonal insult.
Topics: Amacrine Cells; Animals; Axon Fasciculation; Cell Death; Cell Survival; MAP Kinase Kinase 4; MAP Kinase Kinase 7; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nerve Crush; Optic Nerve; Optic Nerve Injuries; Proto-Oncogene Proteins c-jun; Retina; Retinal Ganglion Cells; Signal Transduction
PubMed: 30367030
DOI: 10.1038/s41419-018-1079-7 -
Molecular Medicine Reports Mar 2015The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray...
The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray expression profiles of normal samples, and metastatic and non‑metastatic OS samples. The GSE9508 gene expression profile was downloaded from the Gene Expression Omnibus database, which included 11 human metastatic OS samples, seven non‑metastatic OS samples and five normal samples. Pretreatment of the data was performed using the BioConductor package in R language, and the differentially expressed genes (DEGs) were identified by a t‑test. Furthermore, function and pathway enrichment analyses of the DEGs were conducted using a molecule annotation system. A differential co‑expression network was also constructed, and the submodules were screened using MCODE in Cytoscape. A total of 965 genes were identified as DEGs in metastatic OS. The DEGs were shown to participate in the regulation of DNA‑dependent transcription, the composition of the nucleus, cytoplasm and membrane, and protein and nucleotide binding. Furthermore, the screened DEGs were significantly associated with the ribosome, axon guidance and the cytokine‑cytokine receptor interaction pathway. Certain hub genes were identified in the constructed differential co‑expression network, including matrix metalloproteinase 1 (MMP1), smoothened (SMO), ewing sarcoma breakpoint region 1 (EWSR1) and fasciculation and elongation protein ζ‑1 (FEZ1). Brain selective kinase 2 (BRSK2) and aldo‑keto reductase family 1 member B10 (AKRIB10) were present in the screened submodules. The results of the present study suggest that genes, including MMP1, SMO, EWSR1, FEZ1, BRSK2 and AKRIB10, may be potential targets for the diagnosis and treatment of metastatic OS.
Topics: Bone Neoplasms; Cluster Analysis; Computational Biology; Databases, Nucleic Acid; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Molecular Sequence Annotation; Neoplasm Metastasis; Osteosarcoma; Protein Interaction Mapping; Protein Interaction Maps
PubMed: 25434727
DOI: 10.3892/mmr.2014.3009 -
Nature Communications Nov 2020In the developing nervous system, axons navigate through complex terrains that change depending on when and where outgrowth begins. For instance, in the developing...
In the developing nervous system, axons navigate through complex terrains that change depending on when and where outgrowth begins. For instance, in the developing cochlea, spiral ganglion neurons extend their peripheral processes through a growing and heterogeneous environment en route to their final targets, the hair cells. Although the basic principles of axon guidance are well established, it remains unclear how axons adjust strategies over time and space. Here, we show that neurons with different positions in the spiral ganglion employ different guidance mechanisms, with evidence for both glia-guided growth and fasciculation along a neuronal scaffold. Processes from neurons in the rear of the ganglion are more directed and grow faster than those from neurons at the border of the ganglion. Further, processes at the wavefront grow more efficiently when in contact with glial precursors growing ahead of them. These findings suggest a tiered mechanism for reliable axon guidance.
Topics: Animals; Axon Guidance; Basic Helix-Loop-Helix Transcription Factors; Cell Movement; Cochlea; Female; Mice, Transgenic; Nerve Tissue Proteins; Neurites; Neuroglia; Neurons; Organ Culture Techniques; Pregnancy; Spiral Ganglion; Time-Lapse Imaging
PubMed: 33203842
DOI: 10.1038/s41467-020-19521-2