Alternative titles; symbols
HGNC Approved Gene Symbol: ATOH1
Cytogenetic location: 4q22.2 Genomic coordinates (GRCh38) : 4:93,828,753-93,830,964 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q22.2 | ?Deafness, autosomal dominant 89 | 620284 | Autosomal dominant | 3 |
ATOH1 is a basic helix-loop-helix (bHLH) transcription factor essential for the genesis, survival, and maturation of a variety of neuronal and nonneuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing (summary by Xie et al., 2017).
The Drosophila 'atonal' gene is a proneural gene that produces a protein with bHLH domains and plays an essential role in the development of the Drosophila nervous system. Ben-Arie et al. (1996) cloned a human homolog of atonal. They demonstrated that Drosophila atonal is evolutionarily conserved and that its sequence shares high similarity within the bHLH domain with homologs from the red flour beetle, pufferfish, chicken, mouse, and human. Expression analysis revealed that the mouse and chicken homologs are expressed in the dorsal regions of the hindbrain and spinal cord. The human and mouse atonal genes share 89% sequence identity.
Ben-Arie et al. (1996) mapped the human ATOH1 gene to chromosome 4q on the basis of somatic cell hybrid analysis and to 4q22 on the basis of in situ hybridization studies.
Yang et al. (2001) found that loss of Math1 leads to depletion of goblet, enteroendocrine, and Paneth cells without affecting enterocytes. Colocalization of Math1 with Ki-67 in some proliferating cells suggest that secretory cells (goblet, enteroendocrine, and Paneth cells) arise from a common progenitor that expresses Math1, whereas absorptive cells (enterocytes) arise from a progenitor that is Math1-independent. Yang et al. (2001) proposed that a single self-maintaining stem cell gives rise to 2 daughter cells directly or through intermediate progenitors. In one daughter cell, interaction between Delta and Notch homologs elevates HES1 (139605) expression, inhibiting Math1 expression, and this cell adopts an enterocyte fate. In the other daughter cell, lack of Hes1 expression increases Math1 expression, and this cell becomes a committed multipotent progenitor that will differentiate into a secretory lineage cell.
Using in situ hybridization and immunofluorescence, Gowan et al. (2001) compared the embryonic expression of Mash1 (ASCL1; 100790), Math1, and Ngn1 (NEUROG1; 601726) in mouse and concluded that they define 3 distinct, nonoverlapping populations of neural progenitor cells in the dorsal neural tube. Combining their expression data with loss- and gain-of-function experiments in mouse and chick, Gowan et al. (2001) hypothesized that Atoh1 and the neurogenin factors repress each other's expression, resulting in progenitors expressing only 1 bHLH factor. Atoh1 expressing progenitor cells give rise to interneurons that coexpress LH2A/B (LXH2, 603759; LHX9, 606066) and Brn3a (POU4F1; 601632). Atoh1 is required for these interneurons to form. Gowan et al. (2001) concluded that Neurod3, Neurog2, and Atoh1 have distinct roles in specifying neuronal cell subtype in the dorsal neural tube.
Hsiung and Moses (2002) reviewed the role of the atonal gene in retinal development in Drosophila.
Math1 is a proneural transcription factor essential for establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures in mice. Flora et al. (2007) showed that Math1 interacted with the E protein Tcf4 (602272). Tcf4 -/- mice had disrupted pontine nucleus development, and this selective deficit occurred without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Deletion of the other E protein-encoding genes did not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors.
Sekine et al. (2006) found that expression of HATH1 was lost in 5 of 8 gastric cancer (GC) cell lines examined, whereas normal gastric mucosa expressed HATH1. Expression of the gastric mucin genes MUC6 (158374) and MUC5AC (158373) showed a correlation with that of HATH1 in most GC cell lines. Overexpression of Math1 in GC cells strongly enhanced MUC6 and MUC5AC mRNA levels. RNA interference-mediated downregulation of HATH1 in GC cells led to decreased expression of the mucin genes. Sekine et al. (2006) concluded that HATH1 is a transcriptional regulator for MUC5AC and MUC6 in GC cells and that HATH1 loss may be involved in gastric carcinogenesis.
Flora et al. (2009) showed that Atoh1 regulates the signal transduction pathway of sonic hedgehog (SHH; 600725), an extracellular factor that is essential for granule neuron precursor proliferation, and demonstrated that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. The authors concluded that their data shed light on the function of Atoh1 in postnatal cerebellar development and identified a mechanism that can be targeted to regulate medulloblastoma formation.
Kim et al. (2014) reported the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where Notch signaling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages. Transcript profiles in isolated Lgr5+ (606667) intestinal stem cells and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of dimethylation (H3K4me2) and acetylation (H3K27ac) histone marks and DNase I hypersensitivity, signifying accessible, permissive chromatin, at most of the same cis-elements. Enhancers acting uniquely in progenitors were well demarcated in Lgr5+ intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, Atoh1, a secretory-specific transcription factor, controls lateral inhibition through Delta-like (see 606582) Notch (see 190198) ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of Atoh1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Kim et al. (2014) concluded that lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.
In a large 5-generation Iraqi Jewish family with autosomal dominant nonsyndromic progressive hearing loss (DFNA89; 620284), Brownstein et al. (2020) identified a heterozygous 1-bp deletion in the ATOH1 gene (601461.0001) that segregated fully with disease. Functional analysis revealed that the ATOH1 mutation increases the stability of the protein through decreased degradation.
Ben-Arie et al. (1997) generated mice lacking Atoh1 (previously designated Math1). The mutant mice failed to form granule cells and were born with a cerebellum lacking an external germinal layer. Neonates could not breathe and died shortly after birth. Ben-Arie et al. (1997) concluded that Atoh1 is required for the genesis of granule cells, and hence the predominant neuronal population in the cerebellum.
Bermingham et al. (1999) generated a second Math1-null allele by replacing the Math1 coding region with beta-galactosidase (see 230500). Math1(beta-Gal/beta-Gal) mice showed all the phenotypic features reported in the Math1 -/- mice. Beta-Gal expression in the cerebellum and dorsal spinal cord was identical to that of Math1. Beta-Gal was also expressed throughout the prospective sensory epithelia of the otic vesicle at embryonic day 12.5 in both Math1(+/beta-Gal) mice and Math1(beta-Gal/beta-Gal) embryos. By embryonic day 18.5, beta-Gal was restricted to the hair cells of the developing sensory epithelia in Math1(+/beta-Gal) mice. However, Math1(beta-Gal/beta-Gal) mice retained beta-Gal expression in some supporting cell layers of the sensory epithelium. In the cochlea, beta-Gal expression was absent in the basal turn, greatly decreased in the middle turn, and similar to that in heterozygotes in the apical turn at embryonic day 18.5. Gross morphologic analysis of the inner ears of Math1(beta-Gal/beta-Gal) mice revealed no obvious defects in overall structure compared with wildtype littermates. The branches of the seventh cranial nerve were present and reached the epithelia. Excised utricles and cochleae of wildtype, Math1(+/beta-Gal), and Math1(beta-Gal/beta-Gal) mice were viewed with Nomarski optics. Hair bundles were present in both organs of wildtype mice and heterozygotes but were completely absent in Math1-null littermates. Scanning electron microscopy of the cochlea and vestibular organs confirmed the absence of hair bundles in null mice. Sensory epithelia in null mice were considerably thinner, lacked the normal stratification of cell nuclei, and stained uniformly, all of which is consistent with the absence of hair cells. The sensory epithelia of the null mutants lacked hair cells entirely but did have supporting cells with a normal appearance, including electron-dense cytoplasm, basal nuclei, and secretory granules. Bermingham et al. (1999) concluded that Math1 is essential for hair cell development in the inner ear, and proposed that Math1 acts as a 'pro-hair cell gene' in the developing sensory epithelia.
Using beta-galactosidase staining of Math1-knockin mice, Ben-Arie et al. (2000) confirmed the expression pattern of Math1 in the central nervous system, with expression detected in neural tube, dorsal spinal cord, brainstem, and cerebellar external granule cells. However, they also detected expression in peripheral nervous system mechanoreceptors, including inner ear hair cells and Merkel cells in all areas of the skin, and articular chondrocytes.
Bermingham et al. (2001) studied the developing spinal cord in mice lacking Math1. Using immunohistochemical studies and in situ hybridization, they demonstrated that Math1-deficient embryos lacked expression of Lh2a (LXH2; 603759), Lh2b (LHX9; 606066), and Barhl1 (605211) in the dorsal spinal cord, indicating that these genes act downstream of Math1. Bermingham et al. (2001) concluded that the precursors to the D1 interneurons fail to be specified in Math1-deficient embryos and that the D1 interneuron precursors give rise to interneurons whose axons form the spinocerebellar tracts.
Woods et al. (2004) found that Math1 was broadly expressed in mouse cochlear progenitor cells within the organ of Corti beginning at embryonic day 13.5. At postnatal day 0 (P0), expression of Math1 was restricted to hair cells in wildtype mice. Math1-null mice had complete disruption of formation of the sensory epithelium of the cochlea, with absence of both hair cells and supporting cells at P0. Ectopic expression of Math1 in nonsensory regions of the cochlea induced the formation of sensory clusters containing both hair cells and supporting cells. Moreover, some supporting cells developed independently of Math1 expression, suggesting induction by hair cells and other supporting cells. Woods et al. (2004) suggested that inhibitory actions, likely mediated by the Notch signaling pathway (see 190198), caused downregulation of Math1 in certain cells and diversion from the hair cell fate.
In young adult guinea pigs subjected to ototoxic drugs resulting in complete bilateral hair cell loss in the high- and mid-frequency regions of the cochlea, Izumikawa et al. (2005) delivered the Atoh1 gene by adenoviral vector infusion to the left cochlea. The number of hair cells in the Atoh1-treated ears at 2 months was significantly greater than that in the contralateral ears, which were devoid of hair cells (p less than 0.0006), and the average auditory-evoked brainstem response (ABR) threshold in Atoh1-treated ears was lower (better) than that of contralateral ears at all frequencies. Izumikawa et al. (2005) stated that this was the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal and suggested that ATOH1 is a master regulatory gene that is both necessary and sufficient for producing hair cells in the mammalian cochlea.
Gubbels et al. (2008) showed that in utero transfer of the Atoh1 gene produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes, and express the ribbon synapse marker carboxy-terminal binding protein-2 (CTBP2; 602619). Moreover, the hair cells are capable of mechanoelectrical transduction and show basolateral conductances with age-appropriate specializations. Gubbels et al. (2008) concluded that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. The authors expected that their in utero gene transfer paradigm would enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness.
Maricich et al. (2009) found that conditional knockout (CKO) of Atoh1 in body skin and footpads of mice resulted in reduced mortality compared with Atoh1-null mice and an absence of Merkel cells in these areas. Immunohistochemistry showed that Merkel cells were not required to specify or maintain touch dome ultrastructure. Skin/nerve preparations from Atoh1-CKO mice lacked characteristic neurophysiologic responses normally mediated by Merkel cell-neurite complexes. Maricich et al. (2009) concluded that Merkel cells are required for proper encoding of Merkel receptor responses and are probably an indispensable part of the somatosensory system.
Maricich et al. (2009) generated 2 mouse lines with conditional deletion of Atoh1 in either Egr2 (129010)-expressing cells or Hoxbb1 (142968)-expressing cells, which populate different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Mice with Atoh1 deletion in Egr2-expressing cells were born at the expected mendelian ratio, had a normal lifespan, and did not display any overt morphologic or behavioral phenotypes. Mice with Atoh1 deletion in Hoxb1-expressing cells were also born at the expected mendelian ratio, but about half died within 24 to 36 hours after birth. Both mouse lines were deaf, had diminished auditory brainstem-evoked responses, and had disrupted CN and AAN morphology and connectivity. In addition, mice with Atoh1 deletion in Egr2-expressing cells lost spiral ganglion neurons in the cochlea and AAN neurons during the first 3 days of life, revealing a critical period in development of these neurons.
By immunoprecipitation analysis, Xie et al. (2017) showed that a single conserved serine of Atoh1, ser193, was phosphorylated in mice. Knockin mice homozygous for a phospho-dead ser193-to-ala (S193A) mutation in Atoh1 did not show the postnatal lethality seen in Atoh1-null mice. Atoh1 S193A/+ and Atoh1 S193A/- mice were born at the expected mendelian ratios with normal body weights and no irregular movements or behavior in their home cages. However, further analysis of S193A/- mice revealed motor coordination deficits and cerebellar foliation defects. The majority of Atoh1-dependent neuronal progenitors were unaffected in Atoh1 S193A/- mice, but migration of pontine nucleus progenitors was partially affected. Atoh1 S193A/- mice were profoundly deaf, Atoh1 S193A/S193A mice had an intermediate hearing loss phenotype, and Atoh1 +/- mice had adult-onset deafness. All 3 genotypes exhibited progressive loss of inner ear hair cells commensurate with the level of hearing loss. Similar to Atoh1-null mice, Atoh1 S193A/- mice also lost cochlear hair cells as early as E16.5 due to apoptosis. However, they did not show hair cell loss in the vestibular system, suggesting that impaired vestibular function was not a contributing factor to the motor coordination deficits observed in Atoh1 S193A/- mice. Mechanistically, the Atoh1 S193A mutation did not alter Atoh1 half-life or play a role in Atoh1 protein degradation. Instead, Atoh1 S193A was a hypomorphic allele that partially impaired the ability of Atoh1 to upregulate transcription of its target genes in inner ear, thereby affecting differentiation and survival of hair cells.
In a large 5-generation Iraqi Jewish family (HL263) with autosomal dominant nonsyndromic progressive hearing loss (DFNA89; 620284), Brownstein et al. (2020) identified a heterozygous 1-bp deletion (c.1030delC, NM_005172.1) in the ATOH1 gene, causing a frameshift predicted to alter the last 10 residues of the normally 354-amino acid protein and add 6 residues to its length before a stop (His344fs17Ter). The variant was not found in ethnicity-matched hearing controls or in 105 unrelated individuals from another cohort with hearing loss. Transfected cochlear explants from Atoh -/- mice demonstrated induction of hair cells in response to wildtype or mutant ATOH1; however, Western blot of ATOH1 extracted from HEK293T cells showed a significantly slower rate of degradation for the mutant protein compared to wildtype.
Ben-Arie, N., Bellen, H. J., Armstrong, D. L., McCall, A. E., Gordadze, P. R., Guo, Q., Matzuk, M. M., Zoghbi, H. Y. Math1 is essential for genesis of cerebellar granule neurons. Nature 390: 169-172, 1997. [PubMed: 9367153] [Full Text: https://doi.org/10.1038/36579]
Ben-Arie, N., Hassan, B. A., Bermingham, N. A., Malicki, D. M., Armstrong, D., Matzuk, M., Bellen, H. J., Zoghbi, H. Y. Functional conservation of atonal and Math1 in the CNS and PNS. Development 127: 1039-1048, 2000. [PubMed: 10662643] [Full Text: https://doi.org/10.1242/dev.127.5.1039]
Ben-Arie, N., McCall, A. E., Berkman, S., Eichele, G., Bellen, H. J., Zoghbi, H. Y. Evolutionary conservation of sequence and expression of the bHLH protein atonal suggests a conserved role in neurogenesis. Hum. Molec. Genet. 5: 1207-1216, 1996. [PubMed: 8872459] [Full Text: https://doi.org/10.1093/hmg/5.9.1207]
Bermingham, N. A., Hassan, B. A., Price, S. D., Vollrath, M. A., Ben-Arie, N., Eatock, R. A., Bellen, H. J., Lysakowski, A., Zoghbi, H. Y. Math1: an essential gene for the generation of inner ear hair cells. Science 284: 1837-1841, 1999. [PubMed: 10364557] [Full Text: https://doi.org/10.1126/science.284.5421.1837]
Bermingham, N. A., Hassan, B. A., Wang, V. Y., Fernandez, M., Banfi, S., Bellen, H. J., Fritzsch, B., Zoghbi, H. Y. Proprioceptor pathway development is dependent on MATH1. Neuron 30: 411-422, 2001. [PubMed: 11395003] [Full Text: https://doi.org/10.1016/s0896-6273(01)00305-1]
Brownstein, Z., Gulsuner, S., Walsh, T., Martins, F. T. A., Taiber, S., Isakov, O., Lee, M. K., Bordeynik-Cohen, M., Birkan, M., Chang, W., Casadei, S., Danial-Farran, N., and 38 others. Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1. Clin. Genet. 98: 353-364, 2020. [PubMed: 33111345] [Full Text: https://doi.org/10.1111/cge.13817]
Flora, A., Garcia, J. J., Thaller, C., Zoghbi, H. Y. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc. Nat. Acad. Sci. 104: 15382-15387, 2007. [PubMed: 17878293] [Full Text: https://doi.org/10.1073/pnas.0707456104]
Flora, A., Klisch, T. J., Schuster, G., Zoghbi, H. Y. Deletion of Atoh1 disrupts Sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326: 1424-1427, 2009. Note: Erratum: Science 327: 1454 only, 2009. [PubMed: 19965762] [Full Text: https://doi.org/10.1126/science.1181453]
Gowan, K., Helms, A. W., Hunsaker, T. L., Collisson, T., Ebert, P. J., Odom, R., Johnson, J. E. Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31: 219-232, 2001. [PubMed: 11502254] [Full Text: https://doi.org/10.1016/s0896-6273(01)00367-1]
Gubbels, S. P., Woessner, D. W., Mitchell, J. C., Ricci, A. J., Brigande, J. V. Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 455: 537-541, 2008. [PubMed: 18754012] [Full Text: https://doi.org/10.1038/nature07265]
Hsiung, F., Moses, K. Retinal development in Drosophila: specifying the first neuron. Hum. Molec. Genet. 11: 1207-1214, 2002. [PubMed: 12015280] [Full Text: https://doi.org/10.1093/hmg/11.10.1207]
Izumikawa, M., Minoda, R., Kawamoto, K., Abrashkin, K. A., Swiderski, D. L., Dolan, D. F., Brough, D. E., Raphael, Y. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Med. 11: 271-276, 2005. [PubMed: 15711559] [Full Text: https://doi.org/10.1038/nm1193]
Kim, T.-H., Li, F., Ferreiro-Neira, I., Ho, L.-L., Luyten, A., Nalapareddy, K., Long, H., Verzi, M., Shivdasani, R. A. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506: 511-515, 2014. [PubMed: 24413398] [Full Text: https://doi.org/10.1038/nature12903]
Maricich, S. M., Wellnitz, S. A., Nelson, A. M., Lesniak, D. R., Gerling, G. J., Lumpkin, E. A., Zoghbi, H. Y. Merkel cells are essential for light-touch responses. Science 324: 1580-1582, 2009. [PubMed: 19541997] [Full Text: https://doi.org/10.1126/science.1172890]
Maricich, S. M., Xia, A., Mathes, E. L., Wang, V. Y., Oghalai, J. S., Fritzsch, B., Zoghbi, H. Y. Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei. J. Neurosci. 29: 11123-11133, 2009. [PubMed: 19741118] [Full Text: https://doi.org/10.1523/JNEUROSCI.2232-09.2009]
Sekine, A., Akiyama, Y., Yanagihara, K., Yuasa, Y. Hath1 up-regulates gastric mucin gene expression in gastric cells. Biochem. Biophys. Res. Commun. 344: 1166-1171, 2006. [PubMed: 16647036] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.238]
Woods, C., Montcouquiol, M., Kelley, M. W. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nature Neurosci. 7: 1310-1318, 2004. [PubMed: 15543141] [Full Text: https://doi.org/10.1038/nn1349]
Xie, W. R., Jen, H. I., Seymour, M. L., Yeh, S. Y., Pereira, F. A., Groves, A. K., Klisch, T. J., Zoghbi, H. Y. An Atoh1-S193A phospho-mutant allele causes hearing deficits and motor impairment. J. Neurosci. 37: 8583-8594, 2017. [PubMed: 28729444] [Full Text: https://doi.org/10.1523/JNEUROSCI.0295-17.2017]
Yang, Q., Bermingham, N. A., Finegold, M. J., Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294: 2155-2158, 2001. [PubMed: 11739954] [Full Text: https://doi.org/10.1126/science.1065718]