Maternal Wnt11b regulates cortical rotation during Xenopus axis formation: analysis of maternal-effect wnt11b mutants.

Asymmetric signalling centres in the early embryo are essential for axis formation in vertebrates. These regions (e.g. amphibian dorsal morula, mammalian anterior visceral endoderm) require stabilised nuclear ß-catenin, but the role of localised Wnt ligand signalling activity in their establishment remains unclear. In Xenopus, dorsal ß-catenin is initiated by vegetal microtubule-mediated symmetry breaking in the fertilised egg, known as 'cortical rotation'. Localised wnt11b mRNA and ligand-independent activators of ß-catenin have been implicated in dorsal ß-catenin activation, but the extent to which each contributes to axis formation in this paradigm remains unclear. Here, we describe a CRISPR-mediated maternal-effect mutation in Xenopus laevis wnt11b.L. We find that wnt11b is maternally required for robust dorsal axis formation and for timely gastrulation, and zygotically for left-right asymmetry. Importantly, we show that vegetal microtubule assembly and cortical rotation are reduced in wnt11b mutant eggs. In addition, we show that activated Wnt coreceptor Lrp6 and Dishevelled lack behaviour consistent with roles in early ß-catenin stabilisation, and that neither is regulated by Wnt11b. This work thus implicates Wnt11b in the distribution of putative dorsal determinants rather than in comprising the determinants themselves. This article has an associated 'The people behind the papers' interview.

Fish hearing revealed: Do we understand hearing in critical fishes and marine tetrapods.

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.

Smoothened overexpression causes trochlear motoneurons to reroute and innervate ipsilateral eyes.

The trochlear projection is unique among the cranial nerves in that it exits the midbrain dorsally to innervate the contralateral superior oblique muscle in all vertebrates. Trochlear as well as oculomotor motoneurons uniquely depend upon Phox2a and Wnt1, both of which are downstream of Lmx1b, though why trochlear motoneurons display such unusual projections is not fully known. We used Pax2-cre to drive expression of ectopically activated Smoothened (SmoM2) dorsally in the midbrain and anterior hindbrain. We documented the expansion of oculomotor and trochlear motoneurons using Phox2a as a specific marker at E9.5. We show that the initial expansion follows a demise of these neurons by E14.5. Furthermore, SmoM2 expression leads to a ventral exit and ipsilateral projection of trochlear motoneurons. We compare that data with Unc5c mutants that shows a variable ipsilateral number of trochlear fibers that exit dorsal. Our data suggest that Shh signaling is involved in trochlear motoneuron projections and that the deflected trochlear projections after SmoM2 expression is likely due to the dorsal expression of Gli1, which impedes the normal dorsal trajectory of these neurons.

Development in the Mammalian Auditory System Depends on Transcription Factors.

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.

Wilhelm His' lasting insights into hindbrain and cranial ganglia development and evolution.

Wilhelm His (1831-1904) provided lasting insights into the development of the central and peripheral nervous system using innovative technologies such as the microtome, which he invented. 150 years after his resurrection of the classical germ layer theory of Wolff, von Baer and Remak, his description of the developmental origin of cranial and spinal ganglia from a distinct cell population, now known as the neural crest, has stood the test of time and more recently sparked tremendous advances regarding the molecular development of these important cells. In addition to his 1868 treatise on 'Zwischenstrang' (now neural crest), his work on the development of the human hindbrain published in 1890 provided novel ideas that more than 100 years later form the basis for penetrating molecular investigations of the regionalization of the hindbrain neural tube and of the migration and differentiation of its constituent neuron populations. In the first part of this review we briefly summarize the major discoveries of Wilhelm His and his impact on the field of embryology. In the second part we relate His' observations to current knowledge about the molecular underpinnings of hindbrain development and evolution. We conclude with the proposition, present already in rudimentary form in the writings of His, that a primordial spinal cord-like organization has been molecularly supplemented to generate hindbrain 'neomorphs' such as the cerebellum and the auditory and vestibular nuclei and their associated afferents and sensory organs.

Gene, cell, and organ multiplication drives inner ear evolution.

We review the development and evolution of the ear neurosensory cells, the aggregation of neurosensory cells into an otic placode, the evolution of novel neurosensory structures dedicated to hearing and the evolution of novel nuclei in the brain and their input dedicated to processing those novel auditory stimuli. The evolution of the apparently novel auditory system lies in duplication and diversification of cell fate transcription regulation that allows variation at the cellular level [transforming a single neurosensory cell into a sensory cell connected to its targets by a sensory neuron as well as diversifying hair cells], organ level [duplication of organ development followed by diversification and novel stimulus acquisition] and brain nuclear level [multiplication of transcription factors to regulate various neuron and neuron aggregate fate to transform the spinal cord into the unique hindbrain organization]. Tying cell fate changes driven by bHLH and other transcription factors into cell and organ changes is at the moment tentative as not all relevant factors are known and their gene regulatory network is only rudimentary understood. Future research can use the blueprint proposed here to provide both the deeper molecular evolutionary understanding as well as a more detailed appreciation of developmental networks. This understanding can reveal how an auditory system evolved through transformation of existing cell fate determining networks and thus how neurosensory evolution occurred through molecular changes affecting cell fate decision processes. Appreciating the evolutionary cascade of developmental program changes could allow identifying essential steps needed to restore cells and organs in the future.

Gaskell revisited: new insights into spinal autonomics necessitate a revised motor neuron nomenclature.

Several concepts developed in the nineteenth century have formed the basis of much of our neuroanatomical teaching today. Not all of these were based on solid evidence nor have withstood the test of time. Recent evidence on the evolution and development of the autonomic nervous system, combined with molecular insights into the development and diversification of motor neurons, challenges some of the ideas held for over 100 years about the organization of autonomic motor outflow. This review provides an overview of the original ideas and quality of supporting data and contrasts this with a more accurate and in depth insight provided by studies using modern techniques. Several lines of data demonstrate that branchial motor neurons are a distinct motor neuron population within the vertebrate brainstem, from which parasympathetic visceral motor neurons of the brainstem evolved. The lack of an autonomic nervous system in jawless vertebrates implies that spinal visceral motor neurons evolved out of spinal somatic motor neurons. Consistent with the evolutionary origin of brainstem parasympathetic motor neurons out of branchial motor neurons and spinal sympathetic motor neurons out of spinal motor neurons is the recent revision of the organization of the autonomic nervous system into a cranial parasympathetic and a spinal sympathetic division (e.g., there is no sacral parasympathetic division). We propose a new nomenclature that takes all of these new insights into account and avoids the conceptual misunderstandings and incorrect interpretation of limited and technically inferior data inherent in the old nomenclature.

The quest for restoring hearing: Understanding ear development more completely.

Neurosensory hearing loss is a growing problem of super-aged societies. Cochlear implants can restore some hearing, but rebuilding a lost hearing organ would be superior. Research has discovered many cellular and molecular steps to develop a hearing organ but translating those insights into hearing organ restoration remains unclear. For example, we cannot make various hair cell types and arrange them into their specific patterns surrounded by the right type of supporting cells in the right numbers. Our overview of the topologically highly organized and functionally diversified cellular mosaic of the mammalian hearing organ highlights what is known and unknown about its development. Following this analysis, we suggest critical steps to guide future attempts toward restoration of a functional organ of Corti. We argue that generating mutant mouse lines that mimic human pathology to fine-tune attempts toward long-term functional restoration are needed to go beyond the hope generated by restoring single hair cells in postnatal sensory epithelia.

Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system.

Understanding the evolution of the neurosensory system of man, able to reflect on its own origin, is one of the major goals of comparative neurobiology. Details of the origin of neurosensory cells, their aggregation into central nervous systems and associated sensory organs and their localized patterning leading to remarkably different cell types aggregated into variably sized parts of the central nervous system have begun to emerge. Insights at the cellular and molecular level have begun to shed some light on the evolution of neurosensory cells, partially covered in this review. Molecular evidence suggests that high mobility group (HMG) proteins of pre-metazoans evolved into the definitive Sox [SRY (sex determining region Y)-box] genes used for neurosensory precursor specification in metazoans. Likewise, pre-metazoan basic helix-loop-helix (bHLH) genes evolved in metazoans into the group A bHLH genes dedicated to neurosensory differentiation in bilaterians. Available evidence suggests that the Sox and bHLH genes evolved a cross-regulatory network able to synchronize expansion of precursor populations and their subsequent differentiation into novel parts of the brain or sensory organs. Molecular evidence suggests metazoans evolved patterning gene networks early, which were not dedicated to neuronal development. Only later in evolution were these patterning gene networks tied into the increasing complexity of diffusible factors, many of which were already present in pre-metazoans, to drive local patterning events. It appears that the evolving molecular basis of neurosensory cell development may have led, in interaction with differentially expressed patterning genes, to local network modifications guiding unique specializations of neurosensory cells into sensory organs and various areas of the central nervous system.

Inner ear development: building a spiral ganglion and an organ of Corti out of unspecified ectoderm.

The mammalian inner ear develops from a placodal thickening into a complex labyrinth of ducts with five sensory organs specialized to detect position and movement in space. The mammalian ear also develops a spiraled cochlear duct containing the auditory organ, the organ of Corti (OC), specialized to translate sound into hearing. Development of the OC from a uniform sheet of ectoderm requires unparalleled precision in the topological developmental engineering of four different general cell types, namely sensory neurons, hair cells, supporting cells, and general otic epithelium, into a mosaic of ten distinctly recognizable cell types in and around the OC, each with a unique distribution. Moreover, the OC receives unique innervation by ear-derived spiral ganglion afferents and brainstem-derived motor neurons as efferents and requires neural-crest-derived Schwann cells to form myelin and neural-crest-derived cells to induce the stria vascularis. This transformation of a sheet of cells into a complicated interdigitating set of cells necessitates the orchestrated expression of multiple transcription factors that enable the cellular transformation from ectoderm into neurosensory cells forming the spiral ganglion neurons (SGNs), while simultaneously transforming the flat epithelium into a tube, the cochlear duct, housing the OC. In addition to the cellular and conformational changes forming the cochlear duct with the OC, changes in the surrounding periotic mesenchyme form passageways for sound to stimulate the OC. We review molecular developmental data, generated predominantly in mice, in order to integrate the well-described expression changes of transcription factors and their actions, as revealed in mutants, in the formation of SGNs and OC in the correct position and orientation with suitable innervation. Understanding the molecular basis of these developmental changes leading to the formation of the mammalian OC and highlighting the gaps in our knowledge might guide in vivo attempts to regenerate this most complicated cellular mosaic of the mammalian body for the reconstitution of hearing in a rapidly growing population of aging people suffering from hearing loss.

Evolution and development of the tetrapod auditory system: an organ of Corti-centric perspective.

The tetrapod auditory system transmits sound through the outer and middle ear to the organ of Corti or other sound pressure receivers of the inner ear where specialized hair cells translate vibrations of the basilar membrane into electrical potential changes that are conducted by the spiral ganglion neurons to the auditory nuclei. In other systems, notably the vertebrate limb, a detailed connection between the evolutionary variations in adaptive morphology and the underlying alterations in the genetic basis of development has been partially elucidated. In this review, we attempt to correlate evolutionary and partially characterized molecular data into a cohesive perspective of the evolution of the mammalian organ of Corti out of the tetrapod basilar papilla. We propose a stepwise, molecularly partially characterized transformation of the ancestral, vestibular developmental program of the vertebrate ear. This review provides a framework to decipher both discrete steps in development and the evolution of unique functional adaptations of the auditory system. The combined analysis of evolution and development establishes a powerful cross-correlation where conclusions derived from either approach become more meaningful in a larger context which is not possible through exclusively evolution or development centered perspectives. Selection may explain the survival of the fittest auditory system, but only developmental genetics can explain the arrival of the fittest auditory system. [Modified after (Wagner 2011)].

The evolution of the various structures required for hearing in Latimeria and tetrapods.

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.

Corrigendum to "The evolution of the various structures required for hearing in Latimeria and tetrapods" [IBRO Neurosci. Rep., vol. 14, June 2023, pp. 325-341].

[This corrects the article DOI: 10.1016/j.ibneur.2023.03.007.].

Ptf1a expression is necessary for correct targeting of spiral ganglion neurons within the cochlear nuclei.

Two transcription factors, Atoh1 and Ptf1a, are essential for cochlear nuclei development. Atoh1 is needed to develop glutamatergic neurons, while Ptf1a is required to generate glycinergic and GABAergic neurons that migrate into the cochlear nucleus. While central projections of inner ear afferents are normal following loss of Atoh1, we wanted to know whether the loss of Ptf1a affects central projections. We found that in Ptf1a mutants, initially, afferents show a normal projection; however, a transient posterior expansion of projections to the dorsal cochlear nucleus occurs at a later stage. In addition, in older (E18.5) Ptf1a mutant mice, excessive neuronal branches form beyond the normal projection to the anterior and posterior ventral cochlear nuclei. Our results on Ptf1a null mice are comparable to that observed in loss of function Prickel1, Npr2, or Fzd3 mouse mutants. The disorganized tonotopic projections that we report in Ptf1a mutant embryos might be functionally relevant, but testing this hypothesis requires Ptf1a KO mice at postnatal stages that unfortunately cannot be performed due to their early death.

Neurosensory development of the four brainstem-projecting sensory systems and their integration in the telencephalon.

Somatosensory, taste, vestibular, and auditory information is first processed in the brainstem. From the brainstem, the respective information is relayed to specific regions within the cortex, where these inputs are further processed and integrated with other sensory systems to provide a comprehensive sensory experience. We provide the organization, genetics, and various neuronal connections of four sensory systems: trigeminal, taste, vestibular, and auditory systems. The development of trigeminal fibers is comparable to many sensory systems, for they project mostly contralaterally from the brainstem or spinal cord to the telencephalon. Taste bud information is primarily projected ipsilaterally through the thalamus to reach the insula. The vestibular fibers develop bilateral connections that eventually reach multiple areas of the cortex to provide a complex map. The auditory fibers project in a tonotopic contour to the auditory cortex. The spatial and tonotopic organization of trigeminal and auditory neuron projections are distinct from the taste and vestibular systems. The individual sensory projections within the cortex provide multi-sensory integration in the telencephalon that depends on context-dependent tertiary connections to integrate other cortical sensory systems across the four modalities.

Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence.

Age-related hearing loss (ARHL) is a common, increasing problem for older adults, affecting about 1 billion people by 2050. We aim to correlate the different reductions of hearing from cochlear hair cells (HCs), spiral ganglion neurons (SGNs), cochlear nuclei (CN), and superior olivary complex (SOC) with the analysis of various reasons for each one on the sensory deficit profiles. Outer HCs show a progressive loss in a basal-to-apical gradient, and inner HCs show a loss in a apex-to-base progression that results in ARHL at high frequencies after 70 years of age. In early neonates, SGNs innervation of cochlear HCs is maintained. Loss of SGNs results in a considerable decrease (~50% or more) of cochlear nuclei in neonates, though the loss is milder in older mice and humans. The dorsal cochlear nuclei (fusiform neurons) project directly to the inferior colliculi while most anterior cochlear nuclei reach the SOC. Reducing the number of neurons in the medial nucleus of the trapezoid body (MNTB) affects the interactions with the lateral superior olive to fine-tune ipsi- and contralateral projections that may remain normal in mice, possibly humans. The inferior colliculi receive direct cochlear fibers and second-order fibers from the superior olivary complex. Loss of the second-order fibers leads to hearing loss in mice and humans. Although ARHL may arise from many complex causes, HC degeneration remains the more significant problem of hearing restoration that would replace the cochlear implant. The review presents recent findings of older humans and mice with hearing loss.

Neurog1, Neurod1, and Atoh1 are essential for spiral ganglia, cochlear nuclei, and cochlear hair cell development.

We review the molecular basis of three related basic helix-loop-helix (bHLH) genes (Neurog1, Neurod1, and Atoh1) and upstream regulators Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires early expression of Neurog1, followed by its downstream target Neurod1, which downregulates Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 and Neurog1 expression for various aspects of development. Several experiments show a partial uncoupling of Atoh1/Neurod1 (spiral ganglia and cochlea) and Atoh1/Neurog1/Neurod1 (cochlear nuclei). In this review, we integrate the cellular and molecular mechanisms that regulate the development of auditory system and provide novel insights into the restoration of hearing loss, beyond the limited generation of lost sensory neurons and hair cells.

Sustained Loss of Bdnf Affects Peripheral but Not Central Vestibular Targets.

The vestibular system is vital for proper balance perception, and its dysfunction contributes significantly to fall-related injuries, especially in the elderly. Vestibular ganglion neurons innervate vestibular hair cells at the periphery and vestibular nuclei and the uvula and nodule of the cerebellum centrally. During aging, these vestibular ganglion neurons degenerate, impairing vestibular function. A complete understanding of the molecular mechanisms involved in neurosensory cell survival in the vestibular system is unknown. Brain-derived neurotrophic factor (BDNF) is specifically required for the survival of vestibular ganglion neurons, as its loss leads to early neuronal death. Bdnf null mice die within 3 weeks of birth, preventing the study of the long-term effects on target cells. We use Pax2-cre to conditionally knock out Bdnf, allowing mice survival to approximately 6 months of age. We show that a long-term loss of Bdnf leads to a significant reduction in the number of vestibular ganglion neurons and a reduction in the number of vestibular hair cells. There was no significant decrease in the central targets lateral vestibular nucleus (LVN) or the cerebellum at 6 months. This suggests that the connectivity between central target cells and other neurons suffices to prevent their loss despite vestibular hair cell and ganglion neuron loss. Whether the central neurons would undergo eventual degeneration in the absence of Bdnf remains to be determined.

Developmental Changes in Peripherin-eGFP Expression in Spiral Ganglion Neurons.

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.

Fzd3 Expression Within Inner Ear Afferent Neurons Is Necessary for Central Pathfinding.

During development the afferent neurons of the inner ear make precise wiring decisions in the hindbrain reflective of their topographic distribution in the periphery. This is critical for the formation of sensory maps capable of faithfully processing both auditory and vestibular input. Disorganized central projections of inner ear afferents in Fzd3 null mice indicate Wnt/PCP signaling is involved in this process and ear transplantation in Xenopus indicates that Fzd3 is necessary in the ear but not the hindbrain for proper afferent navigation. However, it remains unclear in which cell type of the inner ear Fzd3 expression is influencing the guidance of inner ear afferents to their proper synaptic targets in the hindbrain. We utilized Atoh1-cre and Neurod1-cre mouse lines to conditionally knockout Fzd3 within the mechanosensory hair cells of the organ of Corti and within the inner ear afferents, respectively. Following conditional deletion of Fzd3 within the hair cells, the central topographic distribution of inner ear afferents was maintained with no gross morphological defects. In contrast, conditional deletion of Fzd3 within inner ear afferents leads to central pathfinding defects of both cochlear and vestibular afferents. Here, we show that Fzd3 is acting in a cell autonomous manner within inner ear afferents to regulate central pathfinding within the hindbrain.