Unravelling the molecular pathways of auditory and vestibular function: the roles of sall1a and the fgf13 genes in the zebrafish inner ear development
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Alsina i Español, Berta
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231 p.
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Montedeoca Vázquez, N. Unravelling the molecular pathways of auditory and vestibular function: the roles of sall1a and the fgf13 genes in the zebrafish inner ear development. Universitat Pompeu Fabra; 2025. handle: http://hdl.handle.net/10803/693689
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Doctoral program
Programa de Doctorat en Biomedicina
Abstract
L’oïda interna és un òrgan sensorial complex essencial per a les funcions auditiva i vestibular, que depèn de les cèl·lules ciliades per a la mecanotransducció i de les neurones sensorials per a transmetre senyals al sistema nerviós central. Mutacions en gens crítics per al desenvolupament de les cèl·lules ciliades i neurones sensorials poden provocar trastorns de l’audició i l’equilibri. No obstant això, el paper de molts gens implicats en desenvolupament i malaltia de l’oïda interna encara roman àmpliament inexplorat. Aquest és el cas dels gens sall1 i fgf13, ambdós expressats a les cèl·lules i neurones sensorials de l’oïda interna i associats a malalties humanes. Mitjançant la tecnologia CRISPR, vam generar línies transgèniques knockout en peix zebra per a aquests gens per tal d’avaluar els efectes de la seva pèrdua de funció a nivell molecular, cel·lular i conductual des de les 24 hores post-fertilització fins els 6 dies post-fertilització. Vam trobar que els mutants per a sall1a exhibien un nombre reduït de cèl·lules madures, una manca d’equilibri estacionari i una regulació a la baixa de tres gens associats a la pèrdua d’audició, entre altres gens importants per al desenvolupament de les cèl·lules ciliades. D’altra banda, els crispants de fgf13a/b presentaven desfasciculació dels axons i una forma ganglionar anormal. Sorprenentment, els mutants homozigots knockout per a fgf13a/b de la línia estable presentaven una morfologia normal del gangli estatoacústic, suggerint un possible mecanisme compensatori. En conclusió, aquest estudi suggereix que sall1a juga un paper crític en la maduració de les cèl·lules ciliades en el peix zebra, la qual cosa pot proporcionar informació respecte de la patogènesi de la pèrdua d’audició en malalties com ara la síndrome de Townes-Brocks. En relació als paralogs de fgf13, el paper d’aquests gens en el desenvolupament del gangli estatoacústic podria trobar-se esmorteït degut a mecanismes compensatoris potencials mediats per ARNm, tot i que les dades suggereixen que un dels seus papers podria estar relacionat al correcte establiment de projeccions d’axons.
The inner ear is a complex sensory organ essential for auditory and vestibular functions, relying on hair cells for mechanotransduction and sensory neurons to transmit signals to the central nervous system. Mutations in genes critical for the development of hair cells and sensory neurons can lead to hearing and balance disorders. Nevertheless, the roles of many genes in inner ear development and disease remain largely unexplored. This is the case for the sall1 and fgf13 genes, both expressed in hair cells and sensory neurons of the inner ear and associated with human conditions. Using CRISPR technology, we generated zebrafish transgenic knockout lines for these genes to assess the effects of their loss-of-function at the molecular, cellular and behavioural level from 24 hours post-fertilization to 6 days post-fertilization. We found that sall1a mutants exhibited a reduced number of mature hair cells, a lack of stationary balance, and downregulation of three hearing loss-associated genes, among other genes important for hair cell development. On a different note, fgf13a/b crispants presented axonal defasciculation and an abnormal ganglionic shape. Surprisingly, homozygous mutants from the fgf13a/b stable knockout line displayed normal morphology of the statoacoustic ganglion, suggesting a possible compensatory mechanism. In conclusion, this study suggests that sall1a plays a critical role in the maturation of hair cells in zebrafish, which may provide insight into the pathogenesis of hearing loss in conditions like Townes-Brocks syndrome. Regarding fgf13 paralogues, potential mRNA-mediated compensatory mechanisms might be concealing the role of these genes in statoacoustic ganglion development, though data suggest that one of its roles could be related to the establishment of proper axonal projections.
The inner ear is a complex sensory organ essential for auditory and vestibular functions, relying on hair cells for mechanotransduction and sensory neurons to transmit signals to the central nervous system. Mutations in genes critical for the development of hair cells and sensory neurons can lead to hearing and balance disorders. Nevertheless, the roles of many genes in inner ear development and disease remain largely unexplored. This is the case for the sall1 and fgf13 genes, both expressed in hair cells and sensory neurons of the inner ear and associated with human conditions. Using CRISPR technology, we generated zebrafish transgenic knockout lines for these genes to assess the effects of their loss-of-function at the molecular, cellular and behavioural level from 24 hours post-fertilization to 6 days post-fertilization. We found that sall1a mutants exhibited a reduced number of mature hair cells, a lack of stationary balance, and downregulation of three hearing loss-associated genes, among other genes important for hair cell development. On a different note, fgf13a/b crispants presented axonal defasciculation and an abnormal ganglionic shape. Surprisingly, homozygous mutants from the fgf13a/b stable knockout line displayed normal morphology of the statoacoustic ganglion, suggesting a possible compensatory mechanism. In conclusion, this study suggests that sall1a plays a critical role in the maturation of hair cells in zebrafish, which may provide insight into the pathogenesis of hearing loss in conditions like Townes-Brocks syndrome. Regarding fgf13 paralogues, potential mRNA-mediated compensatory mechanisms might be concealing the role of these genes in statoacoustic ganglion development, though data suggest that one of its roles could be related to the establishment of proper axonal projections.
Keywords
Inner ear, Hair cells, Sall1a, Hearing loss, CRISPR, Gangli estatoacústic, Fgf13, Peix zebra, Síndrome de Townes-Brocks, RNA-seq
Subjects
577 - Biochemistry. Molecular biology. Biophysics
Publisher
Universitat Pompeu Fabra
