Conserved role of Sonic Hedgehog in tonotopic organization of the avian basilar papilla and mammalian cochlea

Sound frequency discrimination begins at the organ of Corti in mammals and the basilar papilla in birds. Both of these hearing organs are tonotopically organized such that sensory hair cells at the basal (proximal) end respond to high frequency sound, whereas their counterparts at the apex (distal) respond to low frequencies. Sonic hedgehog (Shh) secreted by the developing notochord and floor plate is required for cochlear formation in both species. In mice, the apical region of the developing cochlea, closer to the ventral midline source of Shh, requires higher levels of Shh signaling than the basal cochlea farther away from the midline. Here, gain-of-function experiments using Shh-soaked beads in ovo or a mouse model expressing constitutively activated Smoothened (transducer of Shh signaling) show up-regulation of apical genes in the basal cochlea, even though these regionally expressed genes are not necessarily conserved between the two species. In chicken, these altered gene expression patterns precede morphological and physiological changes in sensory hair cells that are typically associated with tonotopy such as the total number of stereocilia per hair cell and gene expression of an inward rectifier potassium channel, IRK1, which is a bona fide feature of apical hair cells in the basilar papilla. Furthermore, our results suggest that this conserved role of Shh in establishing cochlear tonotopy is initiated early in development by Shh emanating from the notochord and floor plate.

Download Full-text

Cilia in the developing zebrafish ear

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0163 ◽

2019 ◽

Vol 375 (1792) ◽

pp. 20190163 ◽

Cited By ~ 5

Author(s):

Tanya T. Whitfield

Keyword(s):

Hair Cells ◽

Otic Vesicle ◽

Sensory Hair ◽

Ciliary Motility ◽

Extracellular Signals ◽

Sensory Hair Cell ◽

Sensory Hair Cells ◽

And Function ◽

Cellular Compartments

The inner ear, which mediates the senses of hearing and balance, derives from a simple ectodermal vesicle in the vertebrate embryo. In the zebrafish, the otic placode and vesicle express a whole suite of genes required for ciliogenesis and ciliary motility. Every cell of the otic epithelium is ciliated at early stages; at least three different ciliary subtypes can be distinguished on the basis of length, motility, genetic requirements and function. In the early otic vesicle, most cilia are short and immotile. Long, immotile kinocilia on the first sensory hair cells tether the otoliths, biomineralized aggregates of calcium carbonate and protein. Small numbers of motile cilia at the poles of the otic vesicle contribute to the accuracy of otolith tethering, but neither the presence of cilia nor ciliary motility is absolutely required for this process. Instead, otolith tethering is dependent on the presence of hair cells and the function of the glycoprotein Otogelin. Otic cilia or ciliary proteins also mediate sensitivity to ototoxins and coordinate responses to extracellular signals. Other studies are beginning to unravel the role of ciliary proteins in cellular compartments other than the kinocilium, where they are important for the integrity and survival of the sensory hair cell. This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.

Download Full-text

Zebrafishsmoothenedfunctions in ventral neural tube specification and axon tract formation

Development ◽

10.1242/dev.128.18.3497 ◽

2001 ◽

Vol 128 (18) ◽

pp. 3497-3509 ◽

Cited By ~ 16

Author(s):

Zoltán M. Varga ◽

Angel Amores ◽

Katharine E. Lewis ◽

Yi-Lin Yan ◽

John H. Postlethwait ◽

...

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Hedgehog Signaling ◽

Floor Plate ◽

Slow Muscle ◽

Pituitary Cells ◽

Shh Signaling ◽

Ventral Neural Tube ◽

Hypothalamic Cells

Sonic hedgehog (Shh) signaling patterns many vertebrate tissues. shh mutations dramatically affect mouse ventral forebrain and floor plate but produce minor defects in zebrafish. Zebrafish have two mammalian Shh orthologs, sonic hedgehog and tiggy-winkle hedgehog, and another gene, echidna hedgehog, that could have overlapping functions. To examine the role of Hedgehog signaling in zebrafish, we have characterized slow muscle omitted (smu) mutants. We show that smu encodes a zebrafish ortholog of Smoothened that transduces Hedgehog signals. Zebrafish smoothened is expressed maternally and zygotically and supports specification of motoneurons, pituitary cells and ventral forebrain. We propose that smoothened is required for induction of lateral floor plate and a subpopulation of hypothalamic cells and for maintenance of medial floor plate and hypothalamic cells.

Download Full-text

Identification of a 275-kD protein associated with the apical surfaces of sensory hair cells in the avian inner ear.

The Journal of Cell Biology ◽

10.1083/jcb.110.4.1055 ◽

1990 ◽

Vol 110 (4) ◽

pp. 1055-1066 ◽

Cited By ~ 42

Author(s):

G P Richardson ◽

S Bartolami ◽

I J Russell

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Hair Cells ◽

Proximal Region ◽

Basilar Papilla ◽

Relative Molecular Mass ◽

Apical Surface ◽

Sensory Hair ◽

Sensory Hair Cells ◽

Avian Inner Ear

Immunological techniques have been used to generate both polyclonal and monoclonal antibodies specific for the apical ends of sensory hair cells in the avian inner ear. The hair cell antigen recognized by these antibodies is soluble in nonionic detergent, behaves on sucrose gradients primarily as a 16S particle, and, after immunoprecipitation, migrates as a polypeptide with a relative molecular mass of 275 kD on 5% SDS gels under reducing conditions. The antigen can be detected with scanning immunoelectron microscopy on the apical surface of the cell and on the stereocilia bundle but not on the kinocilium. Double label studies indicate that the entire stereocilia bundle is stained in the lagena macula (a vestibular organ), whereas in the basilar papilla (an auditory organ) only the proximal region of the stereocilia bundle nearest to the apical surface is stained. The monoclonal anti-hair cell antibodies do not stain brain, tongue, lung, liver, heart, crop, gizzard, small intestine, skeletal muscle, feather, skin, or eye tissues but do specifically stain renal corpuscles in the kidney. Experiments using organotypic cultures of the embryonic lagena macula indicate that the antibodies cause a significant increase in the steady-state stiffness of the stereocilia bundle but do not inhibit mechanotransduction. The antibodies should provide a suitable marker and/or tool for the purification of the apical sensory membrane of the hair cell.

Download Full-text

let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear

Development ◽

10.1242/dev.183384 ◽

2020 ◽

Vol 147 (15) ◽

pp. dev183384

Author(s):

Lale Evsen ◽

Xiaojun Li ◽

Shuran Zhang ◽

Sharjil Razin ◽

Angelika Doetzlhofer

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Progenitor Cell ◽

Charge Syndrome ◽

Basilar Papilla ◽

Sensory Hair Cells ◽

Evolutionarily Conserved ◽

Auditory Organ ◽

And Control

ABSTRACTThe evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.

Download Full-text

The composition and role of cross links in mechanoelectrical transduction in vertebrate sensory hair cells

Journal of Cell Science ◽

10.1242/jcs.106120 ◽

2013 ◽

Vol 126 (8) ◽

pp. 1721-1731 ◽

Cited By ~ 25

Author(s):

C. M. Hackney ◽

D. N. Furness

Keyword(s):

Hair Cells ◽

Sensory Hair ◽

Mechanoelectrical Transduction ◽

Sensory Hair Cells ◽

Cross Links

Download Full-text

The Role of Frizzled3 and Frizzled6 in Neural Tube Closure and in the Planar Polarity of Inner-Ear Sensory Hair Cells

Journal of Neuroscience ◽

10.1523/jneurosci.4698-05.2005 ◽

2006 ◽

Vol 26 (8) ◽

pp. 2147-2156 ◽

Cited By ~ 324

Author(s):

Y. Wang

Keyword(s):

Inner Ear ◽

Neural Tube ◽

Hair Cells ◽

Neural Tube Closure ◽

Planar Polarity ◽

Sensory Hair ◽

Sensory Hair Cells ◽

Tube Closure

Download Full-text

Faculty Opinions recommendation of The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033488.388757 ◽

2006 ◽

Author(s):

Jeffrey Axelrod

Keyword(s):

Inner Ear ◽

Neural Tube ◽

Hair Cells ◽

Neural Tube Closure ◽

Planar Polarity ◽

Sensory Hair ◽

Sensory Hair Cells ◽

Tube Closure

Download Full-text

Chicken Auditory Supporting Cells Express Interferon Response Genes during Regeneration towards Nascent Sensory Hair Cells In Vivo

10.1101/2021.09.21.461299 ◽

2021 ◽

Author(s):

Amanda S Janesick ◽

Mirko Scheibinger ◽

Nesrine Benkafadar ◽

Sakin Kirti ◽

Stefan Heller

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Cell Loss ◽

Basilar Papilla ◽

Interferon Response ◽

Hair Cell Loss ◽

Supporting Cells ◽

Sensory Hair ◽

Sensory Hair Cells

The avian hearing organ is the basilar papilla that, in sharp contrast to the mammalian cochlea, can regenerate sensory hair cells and thereby recover from complete deafness within weeks. The mechanisms that trigger, sustain, and terminate the regenerative response in vivo are largely unknown. Here, we profile the changes in gene expression in the chicken basilar papilla after aminoglycoside antibiotic-induced hair cell loss using RNA-sequencing. The most prominent changes in gene expression were linked to the upregulation of interferon response genes which occurred in supporting cells, confirmed by single-cell RNA-sequencing and in situ hybridization. We determined that the JAK/STAT signaling pathway is essential for the interferon gene response in supporting cells, set in motion by hair cell loss. Four days after ototoxic damage, we identified newly regenerated, nascent auditory hair cells that express genes linked to termination of the interferon response. These cells are incipient modified neurons that represent a population of hair cells en route towards obtaining their location-specific and fully functional cell identity. The robust, transient expression of immune-related genes in supporting cells suggests a potential functional involvement of JAK/STAT signaling and interferon in sensory hair cell regeneration.

Download Full-text