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The slc4a2b gene is required for hair cell development in zebrafish.

ABSTRACT: Hair cells (HCs) function as important sensory receptors that can detect movement in their immediate environment. HCs in the inner ear can sense acoustic signals, while in aquatic vertebrates HCs can also detect movements, vibrations, and pressure gradients in the surrounding water. Many genes are responsible for the development of HCs, and developmental defects in HCs can lead to hearing loss and other sensory dysfunctions. Here, we found that the solute carrier family 4, member 2b (slc4a2b) gene, which is a member of the anion-exchange family, is expressed in the otic vesicles and lateral line neuromasts in developing zebrafish embryos. An in silico analysis showed that the slc4a2b is evolutionarily conserved, and we found that loss of function of slc4a2b resulted in a decreased number of HCs in zebrafish neuromasts due to increased HC apoptosis. Taken together, we conclude that slc4a2b plays a critical role in the development of HCs in zebrafish.

SUBMITTER: Qian F

PROVIDER: S-EPMC7732325 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The slc4a2b gene is required for hair cell development in zebrafish.

Qian Fuping F Wang Xin X Yin Zhenhua Z Xie Gangcai G Yuan Huijun H Liu Dong D Chai Renjie R

Aging 20201012 19

Hair cells (HCs) function as important sensory receptors that can detect movement in their immediate environment. HCs in the inner ear can sense acoustic signals, while in aquatic vertebrates HCs can also detect movements, vibrations, and pressure gradients in the surrounding water. Many genes are responsible for the development of HCs, and developmental defects in HCs can lead to hearing loss and other sensory dysfunctions. Here, we found that the solute carrier family 4, member 2b (s ...[more]

PMID: 33044947

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Project description:In humans, the absence or irreversible loss of hair cells, the sensory mechanoreceptors in the cochlea, accounts for a large majority of acquired and congenital hearing disorders. In the auditory and vestibular neuroepithelia of the inner ear, hair cells are accompanied by another cell type called supporting cells. This second cell population has been described as having stem cell-like properties, allowing efficient hair cell replacement during embryonic and larval/fetal development of all vertebrates. However, mammals lose their regenerative capacity in most inner ear neuroepithelia in postnatal life. Remarkably, reptiles, birds, amphibians, and fish are different in that they can regenerate hair cells throughout their lifespan. The lateral line in amphibians and in fish is an additional sensory organ, which is used to detect water movements and is comprised of neuroepithelial patches, called neuromasts. These are similar in ultra-structure to the inner ear's neuroepithelia and they share the expression of various molecular markers. We examined the regeneration process in hair cells of the lateral line of zebrafish larvae carrying a retroviral integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant larvae develop normally and display a morphologically intact lateral line. However, after ablation of hair cells with copper or neomycin, their regeneration in pho mutants is severely impaired. We show that proliferation in the supporting cells is strongly decreased after damage to hair cells and correlates with the reduction of newly formed hair cells in the regenerating phoenix mutant neuromasts. The retroviral integration linked to the phenotype is in a novel gene with no known homologs showing high expression in neuromast supporting cells. Whereas its role during early development of the lateral line remains to be addressed, in later larval stages phoenix defines a new class of proteins implicated in hair cell regeneration.

Project description:Hearing loss is a serious burden to physical and mental health worldwide. Aberrant development and damage of hearing organs are recognized as the causes of hearing loss, the molecular mechanisms underlining these pathological processes remain elusive. Investigation of new molecular mechanisms involved in proliferation, differentiation, migration and maintenance of neuromast primordium and hair cells will contribute to better understanding of hearing loss pathology. This knowledge will enable the development of protective agents and mechanism study of drug ototoxicity. In this study, we demonstrate that the zebrafish gene miles-apart, a homolog of sphingosine-1-phosphate receptor 2 (s1pr2) in mammals, has an important role in the development of otic vesicle, neuromasts and survival of hair cells. Whole-mount in situ hybridization of embryos showed that miles-apart expression occurred mainly in the encephalic region and the somites at 24 h.p.f. (hour post fertilization), in the midbrain/hindbrain boundary, the brainstem and the pre-neuromast of lateral line at 48 h.p.f. in a strict spatiotemporal regulation. Both up- and downregulation of miles-apart led to abnormal otoliths and semicircular canals, excess or few hair cells and neuromasts, and their disarranged depositions in the lateral lines. Miles-apart (Mil) dysregulation also caused abnormal expression of hearing-associated genes, including hmx2, fgf3, fgf8a, foxi1, otop1, pax2.1 and tmieb during zebrafish organogenesis. Moreover, in larvae miles-apart gene knockdown significantly upregulated proapoptotic gene zBax2 and downregulated prosurvival gene zMcl1b; in contrast, the level of zBax2 was decreased and of zMcl1b enhanced by miles-apart overexpression. Collectively, Mil activity is linked to organization and number decision of hair cells within a neuromast, also to deposition of neuromasts and formation of otic vesicle during zebrafish organogenesis. At the larva stage, Mil as an upstream regulator of bcl-2 gene family has a role in protection of hair cells against apoptosis by promoting expression of prosurvival gene zMcl1b and suppressing proapoptotic gene zBax2.

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The slc4a2b gene is required for hair cell development in zebrafish.

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The <i>slc4a2b</i> gene is required for hair cell development in zebrafish.

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