Abstract
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.
Highlights
Age-related hearing loss (ARHL), or presbycusis, is a progressive bilateral symmetrical sensorineural hearing loss [1] characterized by four types of pathology: (1) sensory deficits resulting from loss of outer hair cells as seen in loss of high frequency auditory brainstem response, (2) neural deficits from auditory nerve degeneration resulting in poor speech recognition, (3) degeneration of the stria vascularis leading to flat audiometric losses across frequencies; and (4) cochlear conductive deficits associated with increased stiffness of the basilar membrane resulting in evenly sloping audiometric losses [2]
Semaphorin-3A protein was visible within the organ of Corti (Fig 2G and 2H) and spiral ganglion cell (SGN) (Fig 2J and 2K), but not after the semaphorin-3A antibody was pre-adsorbed by the blocking peptide (Fig 2I and 2L)
These data suggest that Nrp1 is expressed at minimal levels by SGNs and cells of the stria vascularis before birth while Nrp1 levels become elevated in these locations after birth
Summary
Age-related hearing loss (ARHL), or presbycusis, is a progressive bilateral symmetrical sensorineural hearing loss [1] characterized by four types of pathology: (1) sensory deficits resulting from loss of outer hair cells as seen in loss of high frequency auditory brainstem response, (2) neural deficits from auditory nerve degeneration resulting in poor speech recognition, (3) degeneration of the stria vascularis leading to flat audiometric losses across frequencies; and (4) cochlear conductive deficits associated with increased stiffness of the basilar membrane resulting in evenly sloping audiometric losses [2]. Familial studies of presbycusis have attributed approximately half of audiometric variances to hereditary factors; the highly variable age of onset, disease progression, and severity of ARHL demonstrate the current uncertain contribution of individual genetic factors to cochlear integrity [3]. Our group has recently demonstrated that ARHL in humans is a polygenic trait [4]. A genetic component to ARHL in inbred mice has been described with approximately 18 Mendelian loci reported to date [5,6,7,8]. It has been our overriding hypothesis that true ARHL in mice, as in humans, is a polygenic trait with the composite phenotype resulting from genomic variation at multiple loci likely different from the Mendelian loci described far
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