Journal of Vestibular ResearchFritzsch et al.Original Research
Palaeospondylus may be a new lineage of jawed vertebrates.
Explores phylogenetic links in jawed vertebrates, indicating new evolutionary insights.
619 pubs · 23,010 cites · h-index 85
Journal of Vestibular ResearchFritzsch et al.Original Research
Explores phylogenetic links in jawed vertebrates, indicating new evolutionary insights.
Developmental DynamicsLee et al.Original Research
BACKGROUND: Knockin mouse models expressing calbindin (Calb1), calretinin (Calb2), and peripherin (Prph) exhibit changes in hair cells (HCs), spiral ganglion neurons (SGN), vestibular ganglion neurons (VGNs), and their central projections. RESULTS: Developing cristae HCs show strong Calb1-positive expression, but adult HCs are mainly Calb2-positive. Utricle and saccule initially have Calb2-positive HCs and later develop Calb1-positive HCs in the striola region. Inner hair cells (IHCs) and outer hair cells (OHCs) in the cochlea express Calb2 early on. Calb1 expression in OHCs overlaps with Calb2; the expression of Myo7a, Calb1, and Calb2 reaches the apex later. SGNs and VGNs exhibit distinct Calb1 and Calb2 patterns but include a subpopulation with mixed expression. Central fibers are Calb1- and Calb2-positive early in the developing cochlear nuclei (CN) and vestibular nuclei (VN) but remain highly Prph-positive. VGNs innervate the lateral and VN, which are positive for Calb2 and Prph. Distinct Calb1-positive neurons overlap with the anterior (A) and ventral (V) cochlear nuclei (AVCN, PVCN) with Calb2, while the dorsal cochlear nucleus (DCN) shows segregation of Calb2 and Calb1. CONCLUSION: We offer insights into the timing of how neuronal identity and connectivity are regulated in the auditory and vestibular systems, as shown by the expression of Calb1, Calb2, and Prph.
International Journal of Molecular SciencesElliott et al.Original Research
Basic helix–loop–helix (bHLH) transcription factors, such as those in the atonal family, are important in cellular fate determination. The expression of the sponge ortholog of the atonal bHLH gene family, AmqbHLH1, in Xenopus laevis previously resulted in the formation of ectodermal ectopic neurons. However, the extent to which these neurons persist through development and the effects on the inner ear and lateral line, which require a critical level and timing of bHLH genes, remains unexplored. To test these long-term effects, we injected various concentrations of AmqbHLH1 mRNA into X. laevis embryos and assessed neurosensory development at developmental stages coinciding with fully developed neurosensory structures. The expression of AmqbHLH1 mRNA in X. laevis resulted in a dose-dependent reduction in or loss of ears and the lateral line system without eliminating ectopic neurons. At the lowest concentrations examined, we found that inner ear neurosensory development consisted sometimes of only a few scattered hair cells in a single-layer epithelium. Furthermore, low concentrations of AmqbHLH1 mRNA affected inner ear afferent guidance. Our data suggest that the AmqbHLH1 gene has some anti-neurosensory abilities in frogs and that the overexpression of a single gene may not be sufficient for stable long-term transdifferentiation in cells.
Frontiers in Cell and Developmental BiologyRenauld et al.Original Research
The transcription factor Lmx1a is widely expressed during early inner ear development, and mice lacking Lmx1a expression exhibit fusion of cochlear and vestibular hair cells and fail to form the ductus reuniens and the endolymphatic sac. Lmx1a dreher ( Lmx1a dr/dr ), a recessive null mutation, results in non-functional Lmx1a expression, which expands from the outer sulcus to the stria vascularis and Reissner’s membrane. In the absence of Lmx1a , we observe a lack of proteins specific to the stria vascularis, such as BSND and KCNQ1 in marginal cells and CD44 in intermediate cells. Further analysis of the superficial epithelial cell layer at the expected stria vascularis location shows that the future intermediate cells migrate during embryonic development but subsequently disappear. Using antibodies against pendrin ( Slc26a4 ) in Lmx1a knockout (KO) mice, we observe an expansion of pendrin expression across the stria vascularis and Reissner’s membrane. Moreover, in the absence of Lmx1a expression, no endocochlear potential is observed. These findings highlight the critical role of Lmx1a in inner ear development, particularly in the differentiation of cochlear and vestibular structures, the recruitment of pigment cells, and the expression of proteins essential for hearing and balance.
eLifeChen et al.Original Research
Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
Journal of Experimental NeurologyYamoah et al.Review
Understanding the development of the auditory system is crucial for uncovering the molecular origins of hearing and its related disorders. During this development, spiral ganglion neurons extend peripheral fibers to cochlear hair cells and central projections to the cochlear nuclei, setting up a tonotopic map that connects the ear to the brainstem, enabling frequency-specific sound perception. This sensory information is then integrated bilaterally through a relay involving the superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and the auditory cortex. While anatomical connectivity has been well-documented, recent advancements have revealed gene regulatory networks that coordinate the specification, differentiation, and connectivity of auditory neurons. In this review, we examine the molecular cascades guiding auditory system development, emphasizing transcriptional hierarchies and lineage determinants. Insights into these mechanisms enhance our understanding of auditory circuit formation and provide a critical foundation for therapeutic strategies aimed at addressing congenital and acquired hearing loss.
The Journal of Comparative NeurologyFritzsch et al.Original Research
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.
Liu et al.Original Research
The mammalian inner ear houses the vestibular and cochlear sensory organs dedicated to sensing balance and sound, respectively. These distinct sensory organs arise from a common prosensory region, but the mechanisms underlying their divergence remain elusive. Here, we showed that two evolutionarily conserved homeobox genes, Irx3 and Irx5 , are required for the patterning and segregation of the saccular and cochlear sensory domains, as well as for the formation of auditory sensory cells. Irx3/5 were highly expressed in the cochlea, their deletion resulted in a significantly shortened cochlea with a loss of the ductus reuniens that bridged the vestibule and cochlea. Remarkably, ectopic vestibular hair cells replaced the cochlear non-sensory structure, the Greater Epithelial Ridge. Moreover, most auditory sensory cells in the cochlea were transformed into hair cells of vestibular identity, with only a residual organ of Corti remaining in the mid-apical region of Irx3/5 double knockout mice. Conditional temporal knockouts further revealed that Irx3/5 are essential for controlling cochlear sensory domain formation before embryonic day 14. Our findings demonstrate that Irx3/5 regulate the patterning of vestibular and cochlear sensory cells, providing insights into the separation of vestibular and cochlear sensory organs during mammalian inner ear development.
SHILAP Revista de lepidopterologíaFritzsch et al.Original Research
Key developmental pathways and gene networks underlie the formation of sensory cell types and structures involved in chemosensation, vision and mechanosensation, and of the efferents these sensory inputs can activate. We describe similarities and differences in these pathways and gene networks in selected species of the three main chordate groups, lancelets, tunicates, and vertebrates, leading to divergent development of olfactory receptors, eyes, hair cells and motoneurons. The lack of appropriately posited expression of certain transcription factors in lancelets and tunicates prevents them from developing vertebrate-like olfactory receptors and eyes, although they generate alternative structures for chemosensation and vision. Lancelets and tunicates lack mechanosensory cells associated with the sensation of acoustic stimuli, but have gravisensitive organs and ciliated epidermal sensory cells that may (and in some cases clearly do) provide mechanosensation and thus the capacity to respond to movement relative to surrounding water. Although functionally analogous to the vertebrate vestibular apparatus and lateral line, homology is questionable due to differences in the expression of the key transcription factors Neurog and Atoh1/7, on which development of vertebrate hair cells depends. The vertebrate hair cell-bearing inner ear and lateral line thus likely represent major evolutionary advances specific to vertebrates. Motoneurons develop in vertebrates under the control of the ventral signaling molecule hedgehog/sonic hedgehog (Hh,Shh), against an opposing inhibitory effect mediated by dorsal signaling molecules. Many elements of Shh-signaling and downstream genes involved in specifying and differentiating motoneurons are also exhibited by lancelets and tunicates, but the repertoire of MNs in vertebrates is broader, indicating greater diversity in motoneuron differentiation programs.
Annual Review of NeurosciencePyott et al.Review
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.
Nature CommunicationsLee et al.Original Research
The inner ear is the hub where hair cells (HCs) transduce sound, gravity, and head acceleration stimuli to the brain. Hearing and balance rely on mechanosensation, the fastest sensory signals transmitted to the brain. The mechanoelectrical transducer (MET) channel is the entryway for the sound-balance-brain interface, but the channel-complex composition is not entirely known. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as MET-complex components. The Pz channels, expressed in HC stereocilia, and cell lines are co-localized and co-assembled with MET complex partners. Mice expressing non-functional Pz1 and Pz2 at the ROSA26 locus have impaired auditory and vestibular traits that can only be explained if the Pzs are integral to the MET complex. We suggest that Pz subunits constitute part of the MET complex and that interactions with other MET complex components yield functional MET units to generate HC MET currents.
eLifeChen et al.Original Research
Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
eLifeChen et al.Original Research
Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss incurable. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The putative ectopic IHCs have functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P1-7 yielded analogous functional putative ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
The Journal of the Acoustical Society of AmericaFritzsch et al.Original Research
Hearing evolved in lampreys with a frequency range of 50-200 Hz. This hearing range is comparable to that of elasmobranchs, most non-teleosts, and lungfish. Elasmobranchs most likely use the saccule and the papilla neglecta (PN) for hearing. In non-teleosts and teleosts, lungfish, and certain tetrapods the saccule is the likely sensor for sound reception while the lagena and the PN are important for gravistatic sensing. Coelacanth and most tetrapods have a basilar papilla (BP) for hearing. In coelacanth and tetrapods, the hair cells of the BP are in contact with a basilar and a tectorial membrane. These membranes transmit mechanical vibrations. A cochlear aqueduct (CA) provides a connection between the cerebrospinal fluid that has a sodium rich space in coelacanth and tetrapods while the potassium rich endolymph is known in vertebrates. A unique feature is known in basic sarcopterygians, the intracranial joint, that never developed in actinopterygians and has been lost in lungfish and tetrapods. The BP in coelacanths is thought to generate pressure with the intracranial joint that will be transmitted to the CA. Lungs or a swim bladder are not forming in Chondrichthyes, structures that have a major impact on hearing in teleosts and tetrapods.
Chen et al.Original Research
Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation of Cldn9 , a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle. In vivo , Cldn9 knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
Brain SciencesYamoah et al.Original Research
The development of the central auditory system, including the auditory cortex and other areas involved in processing sound, is shaped by genetic and environmental factors, enabling infants to learn how to speak. Before explaining hearing in humans, a short overview of auditory dysfunction is provided. Environmental factors such as exposure to sound and language can impact the development and function of the auditory system sound processing, including discerning in speech perception, singing, and language processing. Infants can hear before birth, and sound exposure sculpts their developing auditory system structure and functions. Exposing infants to singing and speaking can support their auditory and language development. In aging humans, the hippocampus and auditory nuclear centers are affected by neurodegenerative diseases such as Alzheimer's, resulting in memory and auditory processing difficulties. As the disease progresses, overt auditory nuclear center damage occurs, leading to problems in processing auditory information. In conclusion, combined memory and auditory processing difficulties significantly impact people's ability to communicate and engage with their societal essence.
Lee et al.Original Research
The inner ear is the hub where hair cells transduce sound, gravity, and head acceleration stimuli carried by neural codes to the brain. Of all the senses, hearing and balance, which rely on mechanosensation, are the fastest sensory signals transmitted to the central nervous system. The mechanoelectrical transducer (MET) channel in hair cells is the entryway for the sound-balance-brain interface, but the channel's composition has eluded biologists due to its complexity. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as central components of the MET complex. The Pz channel subunits are expressed in hair-cell stereocilia, are co-localized and co-assembled, and are essential components of the MET complex in vitro and in situ, including integration with the transmembrane channel (Tmc1/2) protein. Mice expressing non-functional Pz1 and Pz2, but not functional Pz1 at the ROSA26 locus under the control of hair-cell promoters, have impaired auditory and vestibular traits that can only be explained if Pz channel multimers are integral to the MET complex. We affirm that Pz protein subunits constitute MET channels and that functional interactions with components of the MET complex yield current properties resembling hair-cell MET currents. Our results demonstrate Pz is a MET channel component central to interacting with MET complex proteins. Results account for the MET channel pore and complex.
FritzschReview
Extraocular eye muscles (EOMs) are innervated by axons of three ocular motor nuclei, the oculomotor (CNIII), trochlear (CNIV), and abducens (CNVI) neurons. The purpose of this review is to analyze the origin of ocular motor neurons, define the pattern of innervation of nerve fibers that project to the EOMs, pro-vide an overview of vestibular pathway inputs to ocular motor nuclei, and describe congenital disorders that alter the development of ocular motor neurons. Oculomotor neurons originate in the midbrain and innervate the ipsilateral orbit, except for the superior rectus and the levator palpebrae which are contra-laterally innervated. Trochlear motor neurons originate at the midbrain-hindbrain junction and innervate the contralateral superior oblique muscle. Abducens motor neurons originate variously in the rhombomeres r4-6 and innervate the posterior (or lateral) rectus muscle and innervate the retractor bulbi. Genes allow yielding a distinction between special somatic (CNIII, IV) and somatic (CNVI) ocular motor neurons. The ocular motor neurons are innervating somites, which receive innervates vestibular nuclei that connects with the brainstem motor neurons. Development of ocular motor neurons and their axonal projections to the EOMs may be derailed by various genetic causes, resulting in the congenital cranial dysinnervation disorders.
International Journal of Molecular SciencesZine et al.Review
Sensorineural hearing loss is the most prevalent sensory deficit in humans. Most cases of hearing loss are due to the degeneration of key structures of the sensory pathway in the cochlea, such as the sensory hair cells, the primary auditory neurons, and their synaptic connection to the hair cells. Different cell-based strategies to replace damaged inner ear neurosensory tissue aiming at the restoration of regeneration or functional recovery are currently the subject of intensive research. Most of these cell-based treatment approaches require experimental in vitro models that rely on a fine understanding of the earliest morphogenetic steps that underlie the in vivo development of the inner ear since its initial induction from a common otic-epibranchial territory. This knowledge will be applied to various proposed experimental cell replacement strategies to either address the feasibility or identify novel therapeutic options for sensorineural hearing loss. In this review, we describe how ear and epibranchial placode development can be recapitulated by focusing on the cellular transformations that occur as the inner ear is converted from a thickening of the surface ectoderm next to the hindbrain known as the otic placode to an otocyst embedded in the head mesenchyme. Finally, we will highlight otic and epibranchial placode development and morphogenetic events towards progenitors of the inner ear and their neurosensory cell derivatives.
IBRO Neuroscience ReportsFritzsch et al.Original Research
Sarcopterygians evolved around 415 Ma and have developed a unique set of features, including the basilar papilla and the cochlear aqueduct of the inner ear. We provide an overview that shows the morphological integration of the various parts needed for hearing, e.g., basilar papilla, tectorial membrane, cochlear aqueduct, lungs, and tympanic membranes. The lagena of the inner ear evolved from a common macula of the saccule several times. It is near this lagena where the basilar papilla forms in Latimeria and tetrapods. The basilar papilla is lost in lungfish, certain caecilians and salamanders, but is transformed into the cochlea of mammals. Hearing in bony fish and tetrapods involves particle motion to improve sound pressure reception within the ear but also works without air. Lungs evolved after the chondrichthyans diverged and are present in sarcopterygians and actinopterygians. Lungs open to the outside in tetraposomorph sarcopterygians but are transformed from a lung into a swim bladder in ray-finned fishes. Elasmobranchs, polypterids, and many fossil fishes have open spiracles. In Latimeria, most frogs, and all amniotes, a tympanic membrane covering the spiracle evolved independently. The tympanic membrane is displaced by pressure changes and enabled tetrapods to perceive airborne sound pressure waves. The hyomandibular bone is associated with the spiracle/tympanic membrane in actinopterygians and piscine sarcopterygians. In tetrapods, it transforms into the stapes that connects the oval window of the inner ear with the tympanic membrane and allows hearing at higher frequencies by providing an impedance matching and amplification mechanism. The three characters—basilar papilla, cochlear aqueduct, and tympanic membrane—are fluid related elements in sarcopterygians, which interact with a set of unique features in Latimeria. Finally, we explore the possible interaction between the unique intracranial joint, basicranial muscle, and an enlarged notochord that allows fluid flow to the foramen magnum and the cochlear aqueduct which houses a comparatively small brain.