Sensorineural Hearing Loss and Mitochondrial Apoptosis of Cochlear Spiral Ganglion Neurons in Fibroblast Growth Factor 13 Knockout Mice

Abstract

Deafness is known to occur in more than 400 syndromes and accounts for almost 30% of hereditary hearing loss. The molecular mechanisms underlying such syndromic deafness remain unclear. Furthermore, deafness has been a common feature in patients with three main syndromes, the BÖrjeson-Forssman-Lehmann syndrome, Wildervanck syndrome, and Congenital Generalized Hirsutism, all of which are characterized by loss-of-function mutations in the Fgf13 gene. Whether the pathogenesis of deafness in these syndromes is associated with the Fgf13 mutation is not known. To elucidate its role in auditory function, we generated a mouse line with conditional knockout of the Fgf13 gene in the inner ear (Fgf13 cKO). FGF13 is expressed predominantly in the organ of Corti, spiral ganglion neurons (SGNs), stria vascularis, and the supporting cells. Conditional knockout of the gene in the inner ear led to sensorineural deafness with low amplitude and increased latency of wave I in the auditory brainstem response test but had a normal distortion product otoacoustic emission threshold. Fgf13 deficiency resulted in decreased SGN density from the apical to the basal region without significant morphological changes and those in the number of hair cells. TUNEL and caspase-3 immunocytochemistry assays showed that apoptotic cell death mediated the loss of SGNs. Further detection of apoptotic factors through qRT-PCR suggested the activation of the mitochondrial apoptotic pathway in SGNs. Together, this study reveals a novel role for Fgf13 in auditory function, and indicates that the gene could be a potential candidate for understanding deafness. These findings may provide new perspectives on the molecular mechanisms and novel therapeutic targets for treatment deafness.

New developments in the biology of fibroblast growth factors

“…Conditional knockout of Fgf13 in hair cells and supporting cells led to sensorineural deafness without changes in the number or morphology of hair cells. A secondary consequence of conditional knockout of Fgf13 was loss of or aberrant development of spiral ganglion neurons (Yu et al, 2021).…”

ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization

“…Prickle1 is an essential regulator of neuron migration and neurons’ distal and central projections in the cochlea ( 30 ). Some of the identified genes encoding regulatory molecules shown to be essential for neuronal development, the formation of SGNs, and their projections were down-regulated in ISL1CKO neurons, such as the signaling molecules Shh ( 31 ), Wnt3 ( 3 ), and Fgfs ( Fgf10 , Fgf11 , and Fgf13 ) ( 32 , 33 ), and the transcription factors Gata3 ( 13 , 14 ), Irx1 , Irx2 , Pou3f2 , Pou4f2 , and Runx1 ( 3 , 4 ).…”

ISL1 is necessary for auditory neuron development and contributes towards tonotopic organization

“…Prickle1 is an essential regulator of neuron migration and neurons’ distal and central projections in the cochlea 31 . Some of the identified genes encoding regulatory molecules shown to be essential for neuronal development, the formation of SGNs, and their projections were downregulated in ISL1CKO neurons, such as the signaling molecules Shh 32 , Wnt3 3 , and Fgfs ( Fgf10, Fgf11 , and Fgf13 ) 33, 34 , and the transcription factors Gata3 12, 13 , Irx1, Irx2, Pou3f2, Pou4f2 22 , and Runx1 3, 4 .…”