Distinct Localization Research Articles

The role of SPP/SPPL intramembrane proteases in membrane protein homeostasis.

Signal peptide peptidase (SPP) and the four SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 constitute a family of aspartyl intramembrane proteases with homology to presenilins. The different members reside in distinct cellular localisations within the secretory pathway and the endo-lysosomal system. Despite individual cleavage characteristics, they all cleave single-span transmembrane proteins with a type II orientation exhibiting a cytosolic N-terminus. Though the identification of substrates is not complete, SPP/SPPL-mediated proteolysis appears to be rather selective. Therefore, according to our current understanding cleavage by SPP/SPPL proteases rather seems to serve a regulatory function than being a bulk proteolytic pathway. In the present review, we will summarise our state of knowledge on SPP/SPPL proteases and in particular highlight recently identified substrates and the functional and/or (patho)-physiological implications of these cleavage events. Based on this, we aim to provide an overview of the current open questions in the field. These are connected to the regulation of these proteases at the cellular level but also in context of disease and patho-physiological processes. Furthermore, the interplay with other proteostatic systems capable of degrading membrane proteins is beginning to emerge.

Wilson disease-causing mutations in the carboxyl terminus of ATP7B regulates its localization and Golgi exit selectively in the unpolarized cells.

Mutational inactivation of the P-type Cu-ATPase ATP7B interferes with its cellular functions to varying extent leading to varied cellular phenotypes. Wilson's disease (WD) primarily affects organs composed of polarized/differentiated epithelial cells. Therefore, phenotypic variability might differ depending on the polarization/differentiation of the cells. The present study investigates the intracellular stability and localization of ATP7B harboring WD mutations in both unpolarized/undifferentiated and polarized/differentiated cell-based models. Green fluorescent protein (GFP)-ATP7B harboring the WD causing mutations, N41S, S653Y, R778Q, G1061E, H1069Q, S1423N, S1426I, and T1434M, are included for investigation. The C-terminal WD mutations (S1423N, S1426I, and T1434M), exhibit distinct localization and Cu(I) responsive anterograde and retrograde trafficking in undifferentiated/unpolarized vs. differentiated/polarized cells. While basal localization of the S1423N mutant gets corrected in the differentiated glia, its Cu(I) responsive anterograde and retrograde trafficking behavior is not identical to the wild-type. But localization and trafficking properties are completely rescued for the S1426I and T1434M mutants in the differentiated cells. Comprehensive meta-analysis on the effect of the reported C-terminal mutations on patient phenotype and cultured cells demonstrate discrete regions having distinct effects. While mutations in the proximal C-terminus affect ATP7B stability, the present study shows that the distal region dictates cell-specific Trans Golgi Network (TGN) localization and exit. The localization and export properties are corrected in the differentiated cells, which is a plausible mechanism for the milder phenotype exhibited by these mutations. It highlights the critical role of the C-terminus in cell-specific TGN retention and exit of ATP7B.

Integration of spatially opposing cues by a single interneuron guides decision-making in C. elegans

The capacity of animals to respond to hazardous stimuli in their surroundings is crucial for their survival. In mammals, complex evaluations of the environment require large numbers and different subtypes of neurons. The nematode C.elegans avoids hazardous chemicals they encounter by reversing their direction of movement. How does the worms' compact nervous system process the spatial information and direct motion change? We show here that a single interneuron, AVA, receives glutamatergic excitatory and inhibitory signals from head and tail sensory neurons, respectively. AVA integrates the spatially distinct and opposing cues, whose output instructs the animal's behavioral decision. We further find that the differential activation of AVA stems from distinct localization of inhibitory and excitatory glutamate-gated receptors along AVA's process and from different threshold sensitivities of the sensory neurons. Our results thus uncover a cellular mechanism that mediates spatial computation of nociceptive cues for efficient decision-making in C.elegans.

Evaluation of the white matter integrity in morbidly obese patients before and after bariatric surgery; a diffusion tensor imaging study.

To investigate the difference in FA (Fractional anisotropy), ADC (Apparent diffusion coefficient), RD (Radial diffusivity) and AD (axial diffusivity) values of white matter (WM) tracts in morbidly obese subjects before and after bariatric surgery (BS). A group of thirty-nine morbidly obese subjects are evaluated before and 4-6 months after BS. ADC, FA, RD and AD values of 17 distinct neuroanatomic localizations are measured and DTI parameters are analyzed. Following the BS, the patients' mean BMI decreased from 47.665.21 to 31.723.97. A significant difference is displayed between the pre-surgery and post-surgery FA values of SLF, SFOF, ALIC, fornix, ILF, CST, MCP (p = 0.010, p < 0.001, p = 0.048, p = 0.014, p = 0.012, p = 0.012, p = 0.040 respectively). Following BS, decrease in FA values in the mentioned areas are detected. ADC values obtained from MCP are significantly lower in the post-BS period compared to pre-BS period (p = 0.018). There was a statistically significant difference between the pre-surgery and post-surgery AD values of SLF, SFOF, ILF, ALIC, EC, CST, and MCP (p = 0.001, p = 0.022, p = 0.001, p = 0.011, p = 0.001, p = 0.000, p = 0.000, respectively). Following the BS, AD values of the SLF, SFOF, ILF, ALIC, EC, CST, and MCP are decreased. RD values measured from GCC are significantly lower in the post-BS period compared to pre-BS period (p = 0.008). Our study supported the hypothesis of the BS-induced reversibility of the low-grade inflammation in WM tracts in the morbidly obese group following BS. Our DTI results may represent the subacute period findings of the reversal of low-grade inflammation after BS.

CTNNB1 and APC Mutations in Sinonasal Myxoma : Expanding the Spectrum of Tumors Driven By WNT/β-catenin Pathway.

Sinonasal myxoma (SNM) is a rare, benign mesenchymal neoplasm with distinct clinicopathologic features and aberrant nuclear localization of β-catenin by immunohistochemistry. The molecular underpinnings have been linked to that of a "myxoid variant" of desmoid fibromatosis. Herein, we describe a series of 8 cases of SNM and propose clinical and biologic differences compared with desmoid fibromatosis. Our patient cohort is comprised of 5 males and 3 females (age range: 10mo to 12y), 6 of whom are aged less than or equal to 24 months. All presented with facial swelling, reflecting lesions involving the maxillary bone, and all underwent resection. All tumors were variably cellular and comprised of bland spindled to stellate cells in a profusely myxoid background with diffuse nuclear β-catenin expression. All cases of SNM were analyzed by next-generation sequencing using the Oncopanel assay. Three cases failed sequencing, 2 of 5 successful cases exhibited exon 3 CTNNB1 alterations involving the ubiquitin recognition motif, and 3 had adenomatous polyposis coli ( APC ) deletions. One patient had APC germline testing which was negative. No germline testing was available for the remaining 7 patients. Follow-up data over a range of 1 month to 23 years was available for 7 of the 8 SNMs. One case patient had local recurrence, and all were alive without evidence of disease. This is in contrast to the high recurrence rate typically seen in desmoid fibromatosis, particularly after resection. Our findings expand the spectrum of tumors with underlying WNT/β-catenin pathway and highlight the histologic, clinical, and genetic differences of SNM compared with desmoid fibromatosis. APC deletion raises the possibility of underlying germline alteration and familial adenomatous polyposis.

Detection and activity of MMP-2 and MMP-9 in Leishmania amazonensis and Leishmania braziliensis promastigotes

Metalloproteinases (MMPs) are remarkable zinc-dependent endopeptidases, critical for degrading components of the extracellular matrix, thus actively influencing cell migration. Their impact on intracellular parasites, such as the enigmatic protozoan Leishmania, elicits intriguing queries. This study explores into the untapped territory of MMP-2 and MMP-9 within Leishmania spp. promastigotes. Notably, we successfully detected and quantified these MMPs, while also evaluating their activity in two distinct Leishmania species—L. amazonensis (La) and L. braziliensis (Lb)—at various growth stages and isolated from distinct clinical tegumentar disease forms. The results unveiled the presence of MMP-2 and MMP-9 in both species, albeit with distinct localization patterns. Specifically, MMP-9 exhibited significantly higher gelatinolytic activity in La when compared to Lb. Moreover, our data cleverly illustrated the presence and release of MMP-2 and MMP-9 by La and Lb promastigotes, exposing their ability to invade and migrate within a collagen matrix. This pioneering study establishes a compelling correlation between MMP-2 and MMP-9 and their potential role in the dynamics of La and Lb infection. Suggesting their potential as prognostic markers for severe leishmaniasis and promising target molecules for therapeutic interventions, this research opens new avenues for combatting this debilitating parasitic disease.

Eosinophil Phenotypes Are Functionally Regulated by Resolvin D2 during Allergic Lung Inflammation.

Eosinophils (Eos) reside in multiple organs during homeostasis and respond rapidly to an inflammatory challenge. Although Eos share chemical staining properties, they also demonstrate phenotypic and functional plasticity that is not fully understood. Here, we used a murine model of allergic lung inflammation to characterize Eos subsets and determine their spatiotemporal and functional regulation during inflammation and its resolution in response to resolvin D2 (RvD2), a potent specialized proresolving mediator. Two Eos subsets were identified by CD101 expression with distinct anatomic localization and transcriptional signatures at baseline and during inflammation. CD101low Eos were predominantly located in a lung vascular niche and responded to allergen challenge by moving into the lung interstitium. CD101high Eos were predominantly located in bronchoalveolar lavage (BAL) and extravascular lung, only present during inflammation, and had transcriptional evidence for cell activation. RvD2 reduced total Eos numbers and changed their phenotype and activation by at least two distinct mechanisms: decreasing interleukin 5-dependent recruitment of CD101low Eos and decreasing conversion of CD101low Eos to CD101high Eos. Collectively, these findings indicate that Eos are a heterogeneous pool of cells with distinct activation states and spatiotemporal regulation during resolution of inflammation and that RvD2 is a potent proresolving mediator for Eos recruitment and activation.

Spatial distribution of rock uplift in the Bongarà district (Peruvian Andes) and implications for the genesis of supergene ore deposits

Topography and river landscape morphometry of two hydrographic basins, the Utcubamba River and the Chiriaco River basins (Bongará district, Amazonas region) allowed to determine the relationship between the irregular distribution of vertical motions (e.g., rock uplift) and the genesis of supergene Zn deposits. The latter derives from variable weathering of pre-existing carbonate-hosted Zn sulfides orebodies, in three distinct localities: Florida Canyon, Mina Grande and Cristal. The research was carried out through the evaluation of the parameters such as elevation, local relief, swath profile, river longitudinal profiles and transformed river profiles (χ-long profiles), and slope/area analysis to derive the normalized channel steepness index (ksn). The NE-ward sharp increase in mean and minimum elevation coupled with a jump in the mean ksn values, suggests that the Chiriaco River basin has experienced more recent rock uplift than the Utcubamba River basin. In fact, the Utcubamba River experienced a long-lasting uplift, resulting in a rugged local relief and lowering the mean and minimum elevations, and exhumation and weathering of the Triassic-hosted sulfide mineral deposits at Florida Canyon. In the Chiriaco River basin, the younger uplift has promoted the weathering of the more surficial Jurassic-hosted Mina Grande and Cristal mineral deposits. The morphometric approach proved to be effective in recognizing fertile areas with near-surface orebodies also in regions characterized by distinct types of ore deposits.

Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects

POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.

Long non-coding RNA FENDRR suppresses cancer-associated fibroblasts and serves as a prognostic indicator in colorectal cancer

Genetically abnormal fibroblasts are notably more prevalent in colorectal cancer (CRC) than in adjacent normal tissue, emphasizing their significance in driving the heterogeneity of the tumor microenvironment. Functioning as a significant regulatory gene in the context of fibrosis, FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) has exhibited abnormal expression in colorectal cancer and interstitial localization in our experiments. However, current research on the role of FENDRR in cancer has focused solely on its impact on cancer cells. Its crucial role in the tumor stroma is yet to be explored. The goal of this study was to understand the relationship between atypical FENDRR expression, its distinct localization, and genetically abnormal fibroblasts in CRC. We aimed to establish the function of FENDRR within the stromal compartment of patients through bioinformatics. Our study confirmed that FENDRR suppresses cancer-associated fibroblasts by inhibiting their activation and collagen generation in CRC. Furthermore, our findings suggest that low FENDRR expression indicates a poor prognosis. Therefore, we propose that FENDRR is a promising therapeutic target for future studies in CRC.

Endogenous epitope tagging of eEF1A2 in mice reveals early embryonic expression of eEF1A2 and subcellular compartmentalisation of neuronal eEF1A1 and eEF1A2

All vertebrate species express two independently-encoded forms of translation elongation factor eEF1A. In humans and mice eEF1A1 and eEF1A2 are 92 % identical at the amino acid level, but the well conserved developmental switch between the two variants in specific tissues suggests the existence of important functional differences. Heterozygous mutations in eEF1A2 result in neurodevelopmental disorders in humans; the mechanism of pathogenicity is unclear, but one hypothesis is that there is a dominant negative effect on eEF1A1 during development. The high degree of similarity between the eEF1A proteins has complicated expression analysis in the past; here we describe a gene edited mouse line in which we have introduced a V5 tag in the gene encoding eEF1A2. Expression analysis using anti-V5 and anti-eEF1A1 antibodies demonstrates that, in contrast to the prevailing view that eEF1A2 is only expressed postnatally, it is expressed from as early as E11.5 in the developing neural tube. Two colour immunofluorescence also reveals coordinated switching between eEF1A1 and eEF1A2 in different regions of postnatal brain. Completely reciprocal expression of the two variants is seen in post-weaning mouse brain with eEF1A1 expressed in oligodendrocytes and astrocytes and eEF1A2 in neuronal soma. Although eEF1A1 is absent from neuronal cell bodies after development, it is widely expressed in axons. This expression does not appear to coincide with myelin sheaths originating from oligodendrocytes but rather results from localised translation within the axon, suggesting that both variants are transcribed in neurons but show completely distinct subcellular localisation at the protein level. These findings will form an underlying framework for understanding how missense mutations in eEF1A2 result in neurodevelopmental disorders.

Dissonant intimacies: Coloniality and the failures of South–South collaboration

North–South research collaborations have come to include both an epistemic and ethical promise – of disrupting hierarchies, inequalities and asymmetries in global knowledge production. In practice, however, these have been ridden with limits, tension and failure. The ‘South–South’ has emerged as a worthy foil: an easy repository of positive affects and of decolonial futurity. This article turns to a feminist collaborative research initiative that seemed primed to fulfil these promises, but in fact, failed to do so. A partnership between African and Indian feminist scholars did not provide meaningful and reciprocal intellectual exchange. On the contrary, it powerfully revealed the coloniality of knowledge and power in higher education and how it manifested, differently, in two distinct locales in the Global South. This partnership constituted less of a shared ground, than one of complex and uneven relationships – a terrain of dissonant intimacies. It is not surprising that these were Southern scholars working in marginalised areas of research, like gender and sexuality. Such a double marginalisation produces specific sets of choices – and ambivalent desires – when it comes to being included in an unequal global epistemic order (and responding to neoliberal demands). This article contributes to larger debates on decolonising higher education, by shifting the scale from the North–South to the complexities of knowledge-making and power within and across the South.

Structurally and Morphologically Distinct Pathological Tau Assemblies Differentially Affect GVB Accumulation.

Tau aggregation is central to the pathogenesis of a large group of neurodegenerative diseases termed tauopathies, but it is still unclear in which way neurons respond to tau pathology and how tau accumulation leads to neurodegeneration. A striking neuron-specific response to tau pathology is presented by granulovacuolar degeneration bodies (GVBs), lysosomal structures that accumulate specific cargo in a dense core. Here we employed different tau aggregation models in primary neurons to investigate which properties of pathological tau assemblies affect GVB accumulation using a combination of confocal microscopy, transmission electron microscopy, and quantitative automated high-content microscopy. Employing GFP-tagged and untagged tau variants that spontaneously form intraneuronal aggregates, we induced pathological tau assemblies with a distinct subcellular localization, morphology, and ultrastructure depending on the presence or absence of the GFP tag. The quantification of the GVB load in the different models showed that an increased GVB accumulation is associated with the untagged tau aggregation model, characterized by shorter and more randomly distributed tau filaments in the neuronal soma. Our data indicate that tau aggregate structure and/or subcellular localization may be key determinants of GVB accumulation.

The AFB1 auxin receptor controls the cytoplasmic auxin response pathway in Arabidopsis thaliana

The phytohormone auxin triggers root growth inhibition within seconds via a non-transcriptional pathway. Among members of the TIR1/AFB auxin receptor family, AFB1 has a primary role in this rapid response. However, the unique features that confer this specific function have not been identified. Here we show that the N-terminal region of AFB1, including the F-box domain and residues that contribute to auxin binding, is essential and sufficient for its specific role in the rapid response. Substitution of the N-terminal region of AFB1 with that of TIR1 disrupts its distinct cytoplasm-enriched localization and activity in rapid root growth inhibition by auxin. Importantly, the N-terminal region of AFB1 is indispensable for auxin-triggered calcium influx, which is a prerequisite for rapid root growth inhibition. Furthermore, AFB1 negatively regulates lateral root formation and transcription of auxin-induced genes, suggesting that it plays an inhibitory role in canonical auxin signaling. These results suggest that AFB1 may buffer the transcriptional auxin response, whereas it regulates rapid changes in cell growth that contribute to root gravitropism.

Lesion Network Mapping for Neurological Deficit in Acute Ischemic Stroke.

To create a comprehensive map of strategic lesion network localizations for neurological deficits, and identify prognostic neuroimaging biomarkers to facilitate the early detection of patients with a high risk of poor functional outcomes in acute ischemic stroke (AIS). In a large-scale multicenter study of 7,807 patients with AIS, we performed voxel-based lesion-symptom mapping, functional disconnection mapping (FDC), and structural disconnection mapping (SDC) to identify distinct lesion and network localizations for National Institutes of Health Stroke Scale (NIHSS) score. Impact scores were calculated based on the odds ratios or t-values of voxels from voxel-based lesion-symptom mapping, FDC, and SDC results. Ordinal regression models were used to investigate the predictive value of the impact scores on functional outcome (defined as the modified Rankin score at 3 months). We constructed lesion, FDC, and SDC maps for each item of the NIHSS score, which provided insights into the neuroanatomical substrate and network localization of neurological function deficits after AIS. The lesion impact score of limb ataxia, the SDC impact score of limb deficit, and FDC impact score of sensation and dysarthria were significantly associated with modified Rankin Scale at 3 months. Adding the SDC impact score, FDC impact score, and lesion impact score to the NIHSS total score improved the performance in predicting functional outcomes, as compared with using the NIHSS score alone. We constructed comprehensive maps of strategic lesion network localizations for neurological deficits that were predictive of functional outcomes in AIS. These results may provide specifically localized targets for future neuromodulation therapies. ANN NEUROL 2023.

Bloodstained flowers and bloodthirsty flies.

This article is a Commentary on Heiduk et al. (2023), 239:1490–1504.

Genuine Many-Body Quantum Scars along Unstable Modes in Bose-Hubbard Systems.

The notion of many-body quantum scars is associated with special eigenstates, usually concentrated in certain parts of Hilbert space, that give rise to robust persistent oscillations in a regime that globally exhibits thermalization. Here we extend these studies to many-body systems possessing a true classical limit characterized by a high-dimensional chaotic phase space, which are not subject to any particular dynamical constraint. We demonstrate genuine quantum scarring of wave functions concentrated in the vicinity of unstable classical periodic mean-field modes in the paradigmatic Bose-Hubbard model. These peculiar quantum many-body states exhibit distinct phase-space localization about those classical modes. Their existence is consistent with Heller's scar criterion and appears to persist in the thermodynamic long-lattice limit. Launching quantum wave packets along such scars leads to observable long-lasting oscillations, featuring periods that scale asymptotically with classical Lyapunov exponents, and displaying intrinsic irregularities that reflect the underlying chaotic dynamics, as opposed to regular tunnel oscillations.

Topological Phase Transition with Larger Winding Number in the Non‐Hermitian Dimerized Lattice

AbstractThe topological phase transitions among normal insulator phase, two kinds of topological insulator phases, and topological semimetal phase are shown based on the non‐Hermitian dimerized Su–Schrieffer–Heeger (SSH) model with the nonreciprocal intercell and long‐range hopping. In contrast to the previous work, it is found that the topological insulator phase in the present SSH model can hold the larger non‐Bloch winding number accompanied by exceptional winding of the generalized Brillouin zone around the gap‐closing points. Compared with the usual topological insulator phase in non‐Hermitian SSH model, the topological insulator with the larger winding number owns two pairs of zero energy modes with a distinct form of edge localization in the gap. The physical mechanism of the distinct edge localization for zero energy modes via a equivalent Hermitian version of the non‐Hermitian SSH model is revealed. Additionally, the process of the phase transition is visualized among normal insulator phase, topological insulator phases, and topological semimetal phase in detail via the evolution of the gap‐closing points on the plane of generalized Brillouin zone. This work further verifies the non‐Bloch theory and enrich the investigation about the topologically nontrivial phase with the larger topological invariant in the non‐Hermitian SSH model.

Surface magnon-polaritons at a dielectric/graphene/gyromagnetic interface in a perpendicular applied magnetic field

We present a theoretical study of the surface magnon-polaritons at an interface formed by vacuum and a gyromagnetic medium (that can be either ferromagnetic or antiferromagnetic), when there is a graphene layer deposited between the media at the interface and a magnetic field is applied perpendicular to the interface. The retarded-mode dispersion relations are calculated by considering a superposition of transverse magnetic and transversal electric electromagnetic waves in both media. Our results reveal the appearance of the surface magnon-polariton modes (with frequencies typically of a few GHz) that do not exist in the absence of graphene at the interface. Also, a typical magnon-polariton dispersion relation with damping is revealed, including a resonant frequency that depends on the applied magnetic field. The effects of varying the doping levels, which modify the Fermi energies in the graphene, and varying the perpendicular applied magnetic field are presented, revealing a strong influence exerted by the presence of graphene on the surface magnon-polariton modes. Other effects include the control of the slope of the dispersion curves (with respect to the in-plane wave vector) for the modes as the Fermi energies of the graphene sheet are changed and the distinctive localization properties for the emerging surface modes.

Regionalized Protein Localization Domains in the Zebrafish Hair Cell Kinocilium.

Sensory hair cells are the receptors for auditory, vestibular, and lateral line sensory organs in vertebrates. These cells are distinguished by "hair"-like projections from their apical surface collectively known as the hair bundle. Along with the staircase arrangement of the actin-filled stereocilia, the hair bundle features a single, non-motile, true cilium called the kinocilium. The kinocilium plays an important role in bundle development and the mechanics of sensory detection. To understand more about kinocilial development and structure, we performed a transcriptomic analysis of zebrafish hair cells to identify cilia-associated genes that have yet to be characterized in hair cells. In this study, we focused on three such genes-ankef1a, odf3l2a, and saxo2-because human or mouse orthologs are either associated with sensorineural hearing loss or are located near uncharacterized deafness loci. We made transgenic fish that express fluorescently tagged versions of their proteins, demonstrating their localization to the kinocilia of zebrafish hair cells. Furthermore, we found that Ankef1a, Odf3l2a, and Saxo2 exhibit distinct localization patterns along the length of the kinocilium and within the cell body. Lastly, we have reported a novel overexpression phenotype of Saxo2. Overall, these results suggest that the hair cell kinocilium in zebrafish is regionalized along its proximal-distal axis and set the groundwork to understand more about the roles of these kinocilial proteins in hair cells.