The cadherin superfamily encodes more than 100 receptors with diverse functions in tissue development and homeostasis. Classical cadherins mediate adhesion by binding interactions that depend on their N-terminal extracellular cadherin (EC) domains, which swap N-terminal β-strands. Sequence alignments suggest that the strand-swap binding mode is not commonly used by functionally divergent cadherins. Here, we have determined the structure of the EC1–EC2 domains of cadherin 23 (CDH23), which binds to protocadherin 15 (PCDH15) to form tip links of mechanosensory hair cells. Unlike classical cadherins, the CDH23 N terminus contains polar amino acids that bind Ca2+. The N terminus of PCDH15 also contains polar amino acids. Mutations in polar amino acids within EC1 of CDH23 and PCDH15 abolish interaction between the two cadherins. PCDH21 and PCDH24 contain similarly charged N termini, suggesting that a subset of cadherins share a common interaction mechanism that differs from the strand-swap binding mode of classical cadherins.

Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function.

Studying genes linked to deafness identifies components of the ear's mechanotransduction apparatus.

Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice.

We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs.

Hair cells of the inner ear are mechanosensors that transduce mechanical forces arising from sound waves and head movement into electrochemical signals to provide our sense of hearing and balance. Each hair cell contains at the apical surface a bundle of stereocilia. Mechanoelectrical transduction takes place close to the tips of stereocilia in proximity to extracellular tip-link filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel1, 2, 3. Recent reports on the composition4, 5, 6, 7, 8, properties and function9, 10, 11 of tip links are conflicting29. Here we demonstrate that two cadherins that are linked to inherited forms of deafness in humans12, 13, 14, 15 interact to form tip links. Immunohistochemical studies using rodent hair cells show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) localize to the upper and lower part of tip links, respectively. The amino termini of the two cadherins co-localize on tip-link filaments. Biochemical experiments show that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. Ions that affect tip-link integrity and a mutation in PCDH15 that causes a recessive form of deafness16 disrupt interactions between CDH23 and PCDH15. Our studies define the molecular composition of tip links and provide a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.

Mechanoelectrical transduction, the conversion of mechanical force into electrochemical signals, underlies a range of sensory phenomena, including touch, hearing and balance. Hair cells of the vertebrate inner ear are specialized mechanosensors that transduce mechanical forces arising from sound waves and head movement to provide our senses of hearing and balance1, 2; however, the mechanotransduction channel of hair cells and the molecules that regulate channel activity have remained elusive. One molecule that might participate in mechanoelectrical transduction is cadherin 23 (CDH23), as mutations in its gene cause deafness and age-related hearing loss3, 4, 5, 6. Furthermore, CDH23 is large enough to be the tip link, the extracellular filament proposed to gate the mechanotransduction channel7. Here we show that antibodies against CDH23 label the tip link, and that CDH23 has biochemical properties similar to those of the tip link. Moreover, CDH23 forms a complex with myosin-1c, the only known component of the mechanotransduction apparatus8, suggesting that CDH23 and myosin-1c cooperate to regulate the activity of mechanically gated ion channels in hair cells.

•The mechanotransduction channel in hair cells consists of several subunits.•TMC1, TMC2, LHFPL5 and TMIE are candidate channel subunits.•Classical models of adaptation might not apply to cochlear hair cells.•Mechanotransduction might have a role in hair bundle morphogenesis.Hair cells in the mammalian cochlea are specialized sensory cells that convert mechanical signals evoked by sound waves into electrochemical signals. Several integral membrane proteins have recently been identified that are closely linked to the mechanotransduction process. Efforts are under way to determine the extent to which they are subunits of the long thought-after mechanotransduction channel. Recent findings also suggest that mechanotransduction may have a role in fine tuning the length of the stereocilia and thus in the regulation of morphological features of hair cells that are inherently linked to the mechanotransduction process.

Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal is crucial for our ability to hear and to maintain balance. Recent findings indicate that two members of the cadherin superfamily are components of the mechanotransduction machinery in sensory hair cells of the vertebrate inner ear. These studies show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) form several of the extracellular filaments that connect the stereocilia and kinocilium of a hair cell into a bundle. One of these filaments is the tip link that has been proposed to gate the mechanotransduction channel in hair cells. The extracellular domains of CDH23 and PCDH15 differ in their structure from classical cadherins and their cytoplasmic domains bind to distinct effectors, suggesting that evolutionary pressures have shaped the two cadherins for their function in mechanotransduction.

•Fate-restricted progenitors in the pallium produce subtypes of excitatory projection neurons.•Fate-restricted progenitors in the subpallium generate subtypes of interneurons.•Pallium and subpallium may contain subsets of multipotent cortical progenitors.•Radial units contain neurons that are generated from diverse and spatially segregated progenitors.Neocortical circuits are assembled from subtypes of glutamatergic excitatory and GABAergic inhibitory neurons with divergent anatomical and molecular signatures and unique physiological properties. Excitatory neurons derive from progenitors in the pallium, whereas inhibitory neurons originate from progenitors in the subpallium. Both classes of neurons subsequently migrate along well-defined routes to their final target area, where they integrate into common neuronal circuits. Recent findings show that neuronal diversity within the lineages of excitatory and inhibitory neurons is in part already established at the level of progenitor cells before migration. This poses challenges for our understanding of how radial units of interconnected excitatory and inhibitory neurons are assembled from progenitors that are spatially segregated and diverse in nature.

Animals use acoustic signals to communicate and to obtain information about their environment. The processing of acoustic signals is initiated at auditory sense organs, where mechanosensory hair cells convert sound-induced vibrations into electrical signals. Although the biophysical principles underlying the mechanotransduction process in hair cells have been characterized in much detail over the past 30 years, the molecular building-blocks of the mechanotransduction machinery have proved to be difficult to determine. We review here recent studies that have both identified some of these molecules and established the mechanisms by which they regulate the activity of the still-elusive mechanotransduction channel.

The neural circuits of the mammalian neocortex are crucial for perception, complex thought, cognition, and consciousness. This circuitry is assembled from many different neuronal subtypes with divergent properties and functions. Here, we review recent studies that have begun to clarify the mechanisms of cell-type specification in the neocortex, focusing on the lineage relationships between neocortical progenitors and subclasses of excitatory projection neurons. These studies reveal an unanticipated diversity in the progenitor pool that requires a revised view of prevailing models of cell-type specification in the neocortex. We propose a “sequential progenitor-diversification model” that integrates current knowledge to explain how projection neuron diversity is achieved by mechanisms acting on proliferating progenitors and their postmitotic offspring. We discuss the implications of this model for our understanding of brain evolution and pathological states of the neocortex.

Achieving the exquisite sensitivity and frequency selectivity of the mammalian ear requires active amplification of input sound. In this issue of Neuron, Dallos and colleagues demonstrate that the molecular motor prestin, which drives shape changes in the soma of mechanosensory hair cells, underlies mechanical feedback mechanisms for sound amplification in mammals.

•TMIE is essential for mechanotransduction by hair cells•TMIE binds to components of the tip-link complex•Interactions of TMIE with tip links are critical for transduction•The mechanotransduction machinery of hair cells is a multisubunit molecular machineHair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell’s mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea’s tonotopic axis.

Interneurons are critical components of the neocortical circuitry but the mechanisms that regulate their distribution in the neocortex are unclear. In this issue of Neuron, Harwell et al. (2015) and Mayer et al. (2015) use barcoded retroviruses to demonstrate widespread clonal dispersion of interneuron siblings in the brain.