Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus

Chumak, Tetyana; Tóthová, Diana; Filova, Iva; Bureš, Zbyněk; Popelář, Jiří; Pavlínková, Gabriela; Syka, Josef

doi:10.3390/ijms22094507

Cited by 3 publications

(3 citation statements)

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“…During inner ear development, ISL1 is expressed in both neuronal and sensory precursors ( 19 , 21 , 22 ). Transgenic modulations of Isl1 indicate important roles of ISL1 in the maintenance and function of neurons and hair cells and as a possible contributing factor in neurodegeneration ( 64 – 67 ). These studies suggest that ISL1 plays a role in developing neurons and sensory cells, but no direct evaluation of ISL1 function has been performed.…”

Section: Discussionmentioning

confidence: 99%

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

Filova

Pysanenko

Tavakoli

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1 Cre strategies. In the absence of Isl1 , spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

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Section: Discussionmentioning

confidence: 99%

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

Filova

Pysanenko

Tavakoli

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…During inner ear development, ISL1 is expressed in both neuronal and sensory precursors 18, 20, 21, 22, 75 . Transgenic modulations of Isl1 indicate important roles of ISL1 in the maintenance and function of neurons and hair cells and as a possible contributing factor in neurodegeneration 23, 76, 77, 78 . These studies suggest that ISL1 plays a role in developing neurons and sensory cells, but no direct evaluation of ISL1 function has been performed.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that Isl1 Cre -mediated Neurod1 deletion ( Neurod1CKO ) results in a disorganized cochleotopic projection from SGNs 18 , affecting acoustic information processing in the central auditory system of adult mice at the physiological and behavioral levels 19 . During inner ear development, ISL1 is expressed in the differentiating neurons and sensory precursors 18, 20, 21, 22, 23 . Isl1 is expressed in all four populations of SGNs (type Ia, Ib, Ic, and type II) identified by single-cell RNA sequencing 4 .…”

Section: Introductionmentioning

confidence: 99%

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

Filova

Pysanenko

Tavakoli

et al. 2021

Preprint

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A cardinal feature of the auditory pathway is frequency selectivity, represented in the form of a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates molecular and cellular features of auditory neurons, including the formation of the spiral ganglion, and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central compensatory plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

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Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain

Pyott,

Pavlinkova,

Yamoah

et al. 2024

Annual Review of Neuroscience

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Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally. Expected final online publication date for the Annual Review of Neuroscience, Volume 47 is July 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus

Cited by 3 publications

References 53 publications

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

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

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

Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain

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