Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea.
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 char...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5695633?pdf=render |
| _version_ | 1818360930122072064 |
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| author | Pezhman Salehi Marshall X Ge Usha Gundimeda Leah Michelle Baum Homero Lael Cantu Joel Lavinsky Litao Tao Anthony Myint Charlene Cruz Juemei Wang Angeliki Maria Nikolakopoulou Carolina Abdala Matthew William Kelley Takahiro Ohyama Thomas Matthew Coate Rick A Friedman |
| author_facet | Pezhman Salehi Marshall X Ge Usha Gundimeda Leah Michelle Baum Homero Lael Cantu Joel Lavinsky Litao Tao Anthony Myint Charlene Cruz Juemei Wang Angeliki Maria Nikolakopoulou Carolina Abdala Matthew William Kelley Takahiro Ohyama Thomas Matthew Coate Rick A Friedman |
| author_sort | Pezhman Salehi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:08:36Z |
| format | Article |
| id | doaj.art-197dc0aae6f442fc9fbd254a8ce05297 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T21:08:36Z |
| publishDate | 2017-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-197dc0aae6f442fc9fbd254a8ce052972022-12-21T23:31:25ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-10-011310e100704810.1371/journal.pgen.1007048Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea.Pezhman SalehiMarshall X GeUsha GundimedaLeah Michelle BaumHomero Lael CantuJoel LavinskyLitao TaoAnthony MyintCharlene CruzJuemei WangAngeliki Maria NikolakopoulouCarolina AbdalaMatthew William KelleyTakahiro OhyamaThomas Matthew CoateRick A FriedmanNeuropilin-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.http://europepmc.org/articles/PMC5695633?pdf=render |
| spellingShingle | Pezhman Salehi Marshall X Ge Usha Gundimeda Leah Michelle Baum Homero Lael Cantu Joel Lavinsky Litao Tao Anthony Myint Charlene Cruz Juemei Wang Angeliki Maria Nikolakopoulou Carolina Abdala Matthew William Kelley Takahiro Ohyama Thomas Matthew Coate Rick A Friedman Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. PLoS Genetics |
| title | Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. |
| title_full | Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. |
| title_fullStr | Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. |
| title_full_unstemmed | Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. |
| title_short | Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. |
| title_sort | role of neuropilin 1 semaphorin 3a signaling in the functional and morphological integrity of the cochlea |
| url | http://europepmc.org/articles/PMC5695633?pdf=render |
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