Lmx1a and Lmx1b are Redundantly Required for the Development of Multiple Components of the Mammalian Auditory System

Chizhikov, Victor V.; Iskusnykh, Igor Y.; Fattakhov, Nikolai; Fritzsch, Bernd

doi:10.1016/j.neuroscience.2020.11.013

Cited by 30 publications

(72 citation statements)

References 65 publications

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“…Using Pax2-cre to delete Dicer [84] conditionally or Gata3 [83] resulted in incomplete HC loss compared to Foxg1-cre conditional deletion of these genes [83,85]. Like the latter conditional mutants, Lmx1a/b null mice show a complete loss of all cochlear HC development [67]. These data indicate that cochlear HCs are affected by single deletions and complex interactions of several genes.…”

Section: Eya1 and Sox2 And Other Transcription Factors Are Essential mentioning

confidence: 85%

“…Similarly, in Lmx1a/b double knockout (DKO) mice, the cochlea exists as a simple sac devoid of HCs and SGNs, whereas the vestibular neurons and vestibular HCs do form [67]. Finally, even if there is no loss of neurons, Schwann cells' absence significantly affects neuronal guidance.…”

Section: Spiral Ganglion Neurons Depend Upon Eya1 and Sox2 And Other mentioning

confidence: 99%

“…Furthermore, loss of Atoh1 or another bHLH gene, Ptf1a, resulted in a loss of excitatory or inhibitory cochlear nucleus neurons, respectively, signifying their importance for regulating cell fate determination [39,131]. Moreover, Lmx1a and Lmx1b LIM-homeodomain transcription factors expressed in the hindbrain roof plate [40] together regulate Atoh1 expression [67]. Lmx1a/b double null mice lack cochlear development and excitatory neurons in the auditory nuclei, most likely due to the lack of Atoh1 in these mice [67].…”

Section: Cochlear Nuclei Depend On Atoh1mentioning

confidence: 99%

“…Moreover, Lmx1a and Lmx1b LIM-homeodomain transcription factors expressed in the hindbrain roof plate [40] together regulate Atoh1 expression [67]. Lmx1a/b double null mice lack cochlear development and excitatory neurons in the auditory nuclei, most likely due to the lack of Atoh1 in these mice [67]. In Lmx1a/b double mutant mice, roof plate does not differentiate into the choroid plexus, which is associated with lack of expression of roof plate/choroid plexus-derived secreted molecules, such as Gdf7 and Bmps, known to induce Atoh1 expression in adjacent neuroepithelium [132][133][134].…”

Section: Cochlear Nuclei Depend On Atoh1mentioning

confidence: 99%

“…Our in situ hybridization for Atoh1 and Neurod1 shows a segregation of these two bHLH genes (right). Modified from [37,40,67,126,131,137].…”

Section: Neurod1 Interacts With Atoh1 In the Cochleamentioning

confidence: 99%

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Development in the Mammalian Auditory System Depends on Transcription Factors

Elliott

Pavlínková

Chizhikov

et al. 2021

IJMS

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We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

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Section: Eya1 and Sox2 And Other Transcription Factors Are Essential mentioning

confidence: 85%

Section: Spiral Ganglion Neurons Depend Upon Eya1 and Sox2 And Other mentioning

confidence: 99%

Section: Cochlear Nuclei Depend On Atoh1mentioning

confidence: 99%

Section: Cochlear Nuclei Depend On Atoh1mentioning

confidence: 99%

“…Our in situ hybridization for Atoh1 and Neurod1 shows a segregation of these two bHLH genes (right). Modified from [37,40,67,126,131,137].…”

Section: Neurod1 Interacts With Atoh1 In the Cochleamentioning

confidence: 99%

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Development in the Mammalian Auditory System Depends on Transcription Factors

Elliott

Pavlínková

Chizhikov

et al. 2021

IJMS

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Molecular ontology of the parabrachial nucleus

Karthik

Huang

Delgado

et al. 2022

J of Comparative Neurology

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Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it remains difficult to determine which PB neurons influence which functions because their subpopulations intermingle extensively. An improved framework for identifying these intermingled subpopulations would help advance our understanding of neural circuit functions linked to this region. Here, we present the foundation of a developmental‐genetic ontology that classifies PB neurons based on their intrinsic, molecular features. By combining transcription factor labeling with Cre fate‐mapping, we find that the PB is a blend of two, developmentally distinct macropopulations of glutamatergic neurons. Neurons in the first macropopulation express Lmx1b (and, to a lesser extent, Lmx1a) and are mutually exclusive with those in a second macropopulation, which derive from precursors expressing Atoh1. This second, Atoh1‐derived macropopulation includes many Foxp2‐expressing neurons, but Foxp2 also identifies a subset of Lmx1b‐expressing neurons in the Kölliker–Fuse nucleus (KF) and a population of GABAergic neurons ventrolateral to the PB (“caudal KF”). Immediately ventral to the PB, Phox2b‐expressing glutamatergic neurons (some coexpressing Lmx1b) occupy the KF, supratrigeminal nucleus, and reticular formation. We show that this molecular framework organizes subsidiary patterns of adult gene expression (including Satb2, Calca, Grp, and Pdyn) and predicts output projections to the amygdala (Lmx1b), hypothalamus (Atoh1), and hindbrain (Phox2b/Lmx1b). Using this molecular ontology to organize, interpret, and communicate PB‐related information could accelerate the translation of experimental findings from animal models to human patients.

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Irx3/5 Null Deletion in Mice Blocks Cochlea‐Saccule Segregation and Disrupts the Auditory Tonotopic Map

Fritzsch,

Weng,

Yamoah

et al. 2024

J of Comparative Neurology

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A gene cadre orchestrates the normal development of sensory and non‐sensory cells in the inner ear, segregating the cochlea with a distinct tonotopic sound frequency map, similar brain projection, and five vestibular end‐organs. However, the role of genes driving the ear development is largely unknown. Here, we show double deletion of the Iroquois homeobox 3 and 5 transcription factors (Irx3/5 DKO) leads to the fusion of the saccule and the cochlear base. The overlying otoconia and tectorial membranes are absent in the Irx3/5 DKO inner ear, and the primary auditory neurons project fibers to both the saccule and cochlear hair cells. The central neuronal projections from the cochlear apex‐base contour are not fully segregated into a dorsal and ventral innervation in the Irx3/5 DKO cochlear nucleus, obliterating the characteristic tonotopic auditory map. Additionally, Irx3/5 deletion reveals a pronounced cochlear‐apex‐vestibular “vestibular‐cochlear” nerve (VCN) bilateral connection that is less noticeable in wild‐type control mice. Moreover, the incomplete segregation of apex and base projections that expands fibers to connect with vestibular nuclei. The results suggest the mammalian cochlear apex is a derived lagena reminiscent of sarcopterygians. Thus, Irx3 and 5 are potential evolutionary branch‐point genes necessary for balance‐sound segregation, which fused into a saccule‐cochlea organization.

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Lmx1a and Lmx1b are Redundantly Required for the Development of Multiple Components of the Mammalian Auditory System

Cited by 30 publications

References 65 publications

Development in the Mammalian Auditory System Depends on Transcription Factors

Development in the Mammalian Auditory System Depends on Transcription Factors

Molecular ontology of the parabrachial nucleus

Irx3/5 Null Deletion in Mice Blocks Cochlea‐Saccule Segregation and Disrupts the Auditory Tonotopic Map

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