Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea
| Autor: | Charlene Cruz, Juemei Wang, Pezhman Salehi, Leah Michelle Baum, Angeliki M. Nikolakopoulou, Homero Lael Cantu, Joel Lavinsky, Rick A. Friedman, Marshall Ge, Thomas M. Coate, Usha Gundimeda, Carolina Abdala, Takahiro Ohyama, Matthew W. Kelley, Anthony Myint, Litao Tao |
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| Přispěvatelé: | Hamilton, Bruce A |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cancer Research Physiology Immunostaining Cardiovascular Inbred C57BL Biochemistry Nervous System Mice Nerve Fibers 0302 clinical medicine Animal Cells Conditional gene knockout Medicine and Health Sciences Small interfering RNAs Genetics (clinical) Mice Knockout Staining Neurons Animal Models Anatomy Cochlea Cell biology Nucleic acids Electrophysiology medicine.anatomical_structure Experimental Organism Systems Inner Ear Female Hair cell Cellular Types Spiral Ganglion Research Article Signal Transduction Neurite lcsh:QH426-470 1.1 Normal biological development and functioning Knockout Neurogenesis Neurophysiology Mouse Models Biology Research and Analysis Methods 03 medical and health sciences Model Organisms Semaphorin Underpinning research Neurites medicine Genetics otorhinolaryngologic diseases Animals Inner ear Non-coding RNA Molecular Biology Ecology Evolution Behavior and Systematics Spiral ganglion Neurosciences Biology and Life Sciences Semaphorin-3A Cell Biology Neuronal Dendrites Neuropilin-1 Gene regulation Mice Inbred C57BL lcsh:Genetics 030104 developmental biology Ears Specimen Preparation and Treatment Cellular Neuroscience Synapses RNA Axon guidance Gene expression sense organs Head 030217 neurology & neurosurgery Neuroscience Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 13, Iss 10, p e1007048 (2017) PLoS genetics, vol 13, iss 10 PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL. Author summary Neuropilin-1 is a member of the neuropilin family acting as an essential cell surface receptor involved in semaphorin-dependent axon guidance and VEGF-dependent angiogenesis and lies within our previously identified ARHL GWAS interval. In this study, we investigated the role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea, specifically the innervation and vascularization patterns. Detailed analyses of the cochleae of 4-month-old Nrp1 CKO mice showed abnormalities in ribbon synapses, innervation of the hair cells, and microvessels of the stria vascularis. We show also that Neuropilin-1/Semaphorin-3A signaling plays an important role in cochlear innervation. |
| Databáze: | OpenAIRE |
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