Biology subjects

He, D. Z. Z.

Publications and source records attributed to He, D. Z. Z..

4 recordsLinked to original sources

bioRxiv2025

Kinocilia of Vestibular Hair Cells: Bridging Structural and Functional Traits of Primary and Motile Cilia

Vestibular hair cells (HCs) convert gravitational and head motion cues into neural signals through mechanotransduction, mediated by the hair bundle--a mechanically integrated organelle composed of stereocilia and a kinocilium. The kinocilium, a specialized form of primary cilium, remains incompletely defined in structure, molecular composition, and function. To elucidate its characteristics, we conducted single-cell RNA sequencing of adult vestibular and cochlear HCs, uncovering a selective enrichment of primary and motile cilia-associated genes in vestibular HCs, particularly those related to the axonemal repeat complex. This enrichment of orthologous axonemal-related genes was conserved in zebrafish and human vestibular HCs, indicating a shared molecular architecture. Immunostaining validated the expression of key motile cilia markers in vestibular kinocilia. Moreover, live imaging of bullfrog and mouse HCs from crista ampullaris revealed spontaneous kinociliary motion. Together, these findings define the kinocilium as a unique organelle with molecular features of primary and motile cilia and suggest its previously unknown role as an active, force-generating element within the hair bundle.

neuroscience↗

bioRxiv2024

Molecular Specializations Underlying Phenotypic Differences in Inner Ear Hair Cells of Zebrafish and Mice

Hair cells (HCs) are the sensory receptors of the auditory and vestibular systems in the inner ears of vertebrates that selectively transduce mechanical stimuli into electrical activity. Although all HCs have the hallmark stereocilia bundle for mechanotransduction, HCs in non-mammals and mammals differ in their molecular specialization in the apical, basolateral and synaptic membranes. HCs of non-mammals, such as zebrafish (zHCs), are electrically tuned to specific frequencies and possess an active process in the stereocilia bundle to amplify sound signals. Mammalian cochlear HCs, in contrast, are not electrically tuned and achieve amplification by somatic motility of outer HCs (OHCs). To understand the genetic mechanisms underlying differences among adult zebrafish and mammalian cochlear HCs, we compared their RNA-seq-characterized transcriptomes, focusing on protein-coding orthologous genes related to HC specialization. There was considerable shared expression of gene orthologs among the HCs, including those genes associated with mechanotransduction, ion transport/channels, and synaptic signaling. For example, both zebrafish and mouse HCs express Tmc1, Lhfpl5, Tmie, Cib2, Cacna1d, Cacnb2, Otof, Pclo and Slc17a8. However, there were some notable differences in expression among zHCs, OHCs, and inner HCs (IHCs), which likely underlie the distinctive physiological properties of each cell type. Tmc2 and Cib3 were not detected in adult mouse HCs but tmc2a and b and cib3 were highly expressed in zHCs. Mouse HCs express Kcna10, Kcnj13, Kcnj16, and Kcnq4, which were not detected in zHCs. Chrna9 and Chrna10 were expressed in mouse HCs. In contrast, chrna10 was not detected in zHCs. OHCs highly express Slc26a5 which encodes the motor protein prestin that contributes to OHC electromotility. However, zHCs have only weak expression of slc26a5, and subsequently showed no voltage dependent electromotility when measured. Notably, the zHCs expressed more paralogous genes including those associated with HC-specific functions and transcriptional activity, though it is unknown whether they have functions similar to their mammalian counterparts. There was overlap in the expressed genes associated with a known hearing phenotype. Our analyses unveil substantial differences in gene expression patterns that may explain phenotypic specialization of zebrafish and mouse HCs. This dataset also includes several protein-coding genes to further the functional characterization of HCs and study of HC evolution from non-mammals to mammals.

neuroscience↗

bioRxiv2023

Targeted Deletion of All Known Thyroid Hormone Receptors Causes Maturation Retardation and Early-onset Degeneration of Cochlear Outer Sulcus

Thyroid hormone (TH) and its receptors (TRs) are crucial for cochlear late-stage development and endocochlear potential (EP) maintenance. However, the mechanism underlying EP reduction in the absence of TH or TRs remains elusive. Cochlear outer sulcus root cells undergo significant morphological changes during late-stage cochlear development and are believed to play a role in maintaining endolymph homeostasis and EP. Yet, it is unknown whether TH and/or TRs are necessary for root cell differentiation and function. Here, we elucidate the essential role of TH or TRs in postnatal root cell development and survival in mice. TH deficiency significantly delayed root cell differentiation. Otocyst-selective deletion of both Thra and Thrb, but not Thrb alone, leads to a similar impairment, accompanied by early degeneration of root cells, with the stria vascularis remaining unaffected. Furthermore, a 22% reduction in mean EP magnitudes was observed in conditional TRs double knockout mice at 4 months of age, less pronounced than in global TRs knockout mice. Transcriptome analysis reveals that TH deficiency downregulates a significant portion of root cell-enriched genes. These findings underscore the redundant roles of TR and TR{beta} in promoting the late-stage differentiation and survival of root cells. Additionally, they suggest that the expression of TRs in cochlear epithelium is crucial for maintaining an optimal EP magnitude, while TRs expressed in areas outside cochlear epithelium, particularly in spiral ligament fibrocytes, may also significantly contribute to EP maintenance. This study advances our understanding of TH in cochlear outer sulcus development and EP maintenance.

developmental biology↗

bioRxiv2020

Transcription Co-Factor LBH Is Necessary for Maintenance of Stereocilia Bundles and Survival of Cochlear Hair Cells

Hearing loss affects ~10% of adults worldwide and is irreversible. Most sensorineural hearing loss is caused by progressive loss of mechanosensitive hair cells (HCs) in the cochlea of the inner ear. The molecular mechanisms underlying HC maintenance and loss are largely unknown. Our previous cell-specific transcriptome analysis showed that Limb-Bud-and-Heart (LBH), a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role. Surprisingly, Lbh deletion did not affect differentiation and early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia bundles. Whole-cell recording showed that the stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. Cell-specific RNA-seq and bioinformatic analyses identified Spp1, Six2, Gps2, Ercc6, Snx6 as well as Plscr1, Rarb, Per2, Gmnn and Map3k5 among the top five transcription factors up- or down-regulated in Lbh-null OHCs. Furthermore, this analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. We speculate that LBH may promote maintenance of HCs and stereocilia bundles by regulating Notch and Wnt signaling activity. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival.

neuroscience↗