Affinage

ATOH1

Transcription factor ATOH1 · UniProt Q92858

Length
354 aa
Mass
38.2 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATOH1 is a proneural basic helix-loop-helix (bHLH) transcription factor that functions as a master regulator of cell fate specification across multiple tissues, including inner ear hair cells, intestinal secretory lineages, cerebellar granule neurons, dorsal spinal interneurons, Merkel cells, and respiratory chemosensory neurons. ATOH1 binds E-box motifs as heterodimers with E-proteins such as Tcf4 and E47 to activate context-specific transcriptional programs encompassing hundreds of target genes — including Barhl1, Gfi1, Mbh1/2, MUC2, and CHRNA1 — and autoregulates its own expression through conserved enhancers containing E-box and Tcf/Lef sites, the latter linking ATOH1 transcription to Wnt/β-catenin signaling (PMID:10683172, PMID:19864427, PMID:21300888, PMID:28174757). ATOH1 protein stability is tightly controlled by phosphorylation-dependent proteasomal degradation mediated by the E3 ubiquitin ligase Huwe1, opposed by SHH signaling, and modulated by BMP, GSK3β/Wnt, and PI3K pathways; multisite phosphorylation governs the balance between secretory progenitor commitment and stem cell self-renewal in the intestine (PMID:24960692, PMID:18347090, PMID:17241872, PMID:30100168). In hair cell and Merkel cell differentiation, ATOH1 initially activates POU4F3, which then pioneers the opening of closed ATOH1 target enhancers in a feed-forward loop, while in the intestine ATOH1 operates genetically downstream of Notch signaling — all Notch-mediated effects on secretory fate require ATOH1 — and upstream of effectors including SPDEF and Gfi1 (PMID:34266958, PMID:21282114, PMID:20975679, PMID:16230531).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    Establishing that ATOH1 is required for hair cell genesis resolved the long-standing question of what transcription factor specifies inner ear sensory cell fate.

    Evidence Math1-null mice completely lack cochlear and vestibular hair cells

    PMID:10364557

    Open questions at the time
    • Sufficiency not yet demonstrated
    • Mechanism of action (direct targets) unknown
    • Whether Math1 specifies vs. differentiates hair cells unresolved
  2. 2000 High

    Demonstrating that ATOH1 overexpression converts non-sensory epithelial cells into hair cells established its sufficiency for hair cell fate and identified autoregulation through conserved enhancer E-boxes as a core transcriptional mechanism.

    Evidence Math1 overexpression in rat cochlear explants produces ectopic hair cells; transgenic reporter assays with E-box mutagenesis define autoregulatory enhancers

    PMID:10683172 PMID:10816314

    Open questions at the time
    • Direct genomic targets beyond auto-enhancer not identified
    • Whether autoregulation is sufficient for maintenance unknown
  3. 2001 High

    Extending ATOH1's requirement beyond the ear to intestinal secretory lineages and dorsal spinal interneurons established it as a multi-tissue cell fate determinant, while cross-inhibition with Ngn1 explained how discrete progenitor domains form.

    Evidence Math1-null mice lack all intestinal secretory cells and dI1 interneurons; reciprocal gain/loss-of-function shows Math1-Ngn1 cross-repression in spinal cord

    PMID:11395003 PMID:11502254 PMID:11739954

    Open questions at the time
    • Whether Math1 acts in secretory progenitors or earlier stem cells unclear
    • Direct target genes in intestine not identified
    • Cross-inhibition mechanism (direct vs. indirect) unresolved
  4. 2002 High

    Functional interchangeability between Drosophila atonal and mouse Math1 across species demonstrated deep conservation of proneural activity, while refined analysis showed Math1 acts within a pre-established sensory primordium to select hair cell fate rather than to form the primordium itself.

    Evidence Cross-species transgenic rescue in flies and mice; Math1-null cochlear analysis with BrdU labeling and fate mapping

    PMID:11973280 PMID:12372255

    Open questions at the time
    • What determines which cells within the primordium express Math1 unknown
    • Structural basis of functional equivalence unresolved
  5. 2003 High

    Identification of direct transcriptional targets (CHRNA1 in hair cells) and repressors (Zic1 blocking autoregulation) revealed both output and input mechanisms controlling ATOH1 activity.

    Evidence EMSA/supershift showing ATOH1/E47 binding to CHRNA1 E-boxes; Zic1 binding to Math1 enhancer blocks autoregulation in chick neural tube

    PMID:12642498 PMID:17961150

    Open questions at the time
    • Genome-wide target repertoire unknown
    • Whether Zic1 repression is context-specific unresolved
  6. 2004 High

    Domain-swap mutagenesis revealed that helix 2 of Math1's bHLH domain is specifically required for neuronal subtype specification, and Math1 was found to regulate Notch pathway components (including physical interaction with Hes5) establishing negative feedback control.

    Evidence bHLH domain swaps tested in chick neural tube electroporation; co-IP of Hes5-Math1 in cerebellar granule cell cultures from Math1/lacZ KO mice

    PMID:14757642 PMID:14993186

    Open questions at the time
    • Structural basis of helix 2 specificity unresolved
    • Hes5-Math1 interaction confirmed by single co-IP in one lab
  7. 2005 High

    Identification of Gfi1 as a downstream effector and Mbh1 as a direct target gene (confirmed by ChIP) began to define the transcriptional cascade downstream of ATOH1 in intestine and spinal cord.

    Evidence Gfi1-null mice show secretory lineage defects epistatic to Math1; ChIP confirms Math1 binding to Mbh1 enhancer E-box

    PMID:15788459 PMID:16230531

    Open questions at the time
    • Comprehensive target gene sets in each tissue not yet defined
    • Whether Gfi1 is a direct ATOH1 target unknown
  8. 2006 Medium

    Discovery of GSK3β-mediated proteasomal degradation of ATOH1 and identification of MUC2 as a direct transcriptional target linked post-translational regulation and intestinal differentiation output.

    Evidence GSK3β/proteasome inhibitor experiments in colon cancer cells; MUC2 promoter mutagenesis reporter assays

    PMID:17000673 PMID:17241872

    Open questions at the time
    • Identity of the E3 ligase mediating GSK3β-directed degradation unknown
    • In vivo relevance of GSK3β-Atoh1 axis not confirmed
  9. 2007 High

    Genetic epistasis established that all intestinal Notch signaling effects on secretory fate are channeled through ATOH1, and that E-protein partner identity (Tcf4) confers regional specificity to ATOH1 function in the hindbrain.

    Evidence RBP-Jκ/Math1 double conditional KO in intestine; Tcf4-null mice with selective pontine nucleus deficits and Tcf4-Math1 co-IP

    PMID:17878293 PMID:21282114

    Open questions at the time
    • How Notch represses Math1 transcription mechanistically not defined
    • Whether other E-proteins substitute for Tcf4 in other brain regions unknown
  10. 2008 High

    BMP signaling was shown to promote ATOH1 protein degradation in cerebellar granule neuron progenitors, while additional direct targets (Mbh1/Mbh2 in cerebellum) and repressors (Prox1 in hair cells) were identified, expanding the regulatory network.

    Evidence Proteasome inhibitor rescue of BMP-induced Atoh1 loss in GNPs; ChIP for Math1 at Mbh loci; Prox1 adenoviral transduction represses Atoh1/Gfi1 reporters

    PMID:18347090 PMID:18652815 PMID:18723012

    Open questions at the time
    • E3 ligase for BMP-mediated degradation not identified
    • Prox1 repression mechanism (direct vs. indirect on Atoh1) unclear
  11. 2009 High

    Demonstration that β-catenin directly binds Tcf/Lef sites in the Atoh1 3′ enhancer established Wnt signaling as a direct transcriptional activator of ATOH1, complementing the earlier finding that Wnt/GSK3β also regulates ATOH1 protein stability.

    Evidence ChIP showing β-catenin at Tcf/Lef sites, siRNA knockdown, site mutagenesis reducing reporter expression

    PMID:19864427

    Open questions at the time
    • How transcriptional activation and protein destabilization by Wnt are balanced in vivo unknown
  12. 2010 High

    Confirming that Math1-deficient intestinal stem cells are refractory to Notch inhibitor-induced goblet cell conversion solidified ATOH1's position as the essential effector downstream of Notch in secretory fate commitment.

    Evidence γ-secretase inhibitor treatment of Math1-deficient mice fails to induce goblet cells

    PMID:20975679

    Open questions at the time
    • Whether Notch directly represses Atoh1 transcription or acts through intermediaries unresolved
  13. 2011 High

    Genome-wide ChIP-seq in cerebellum and spinal cord revealed ATOH1 directly binds over 600 target genes via a defined 10-nucleotide motif (AtEAM), and ATOH1 was shown to be required for intestinal tuft cell differentiation, expanding the known secretory lineage dependence.

    Evidence ChIP-seq in postnatal cerebellum and sorted dI1 populations; Atoh1 conditional KO lacking tuft cells

    PMID:21300888 PMID:21383077 PMID:21795538

    Open questions at the time
    • Tissue-specific co-factors determining which targets are activated in each context not identified
    • Tuft cell-specific targets of ATOH1 unknown
  14. 2012 High

    Identification of Eya1/Six1/Sox2 as synergistic activators of Atoh1 enhancers via direct binding defined an upstream transcriptional module for hair cell induction, while conditional overexpression showed ATOH1 can activate Notch-mediated mosaic formation and proliferation in the postnatal cochlea.

    Evidence Co-IP and enhancer mutagenesis for Eya1/Six1/Sox2; inducible Atoh1 overexpression mouse with BrdU and electrophysiology

    PMID:22340499 PMID:22573692

    Open questions at the time
    • Whether Eya1/Six1 are sufficient without Atoh1 for hair cell fate unclear
    • Age-dependent competence restriction mechanism unknown
  15. 2013 High

    Staged conditional deletion demonstrated that continued ATOH1 expression is required for hair cell survival beyond initial specification, with Barhl1 and Gfi1 maintenance being ATOH1-dependent while Pou4f3 is ATOH1-independent.

    Evidence Conditional Atoh1 deletion at E15.5 and later timepoints with immunostaining for downstream TFs

    PMID:23796904

    Open questions at the time
    • Whether ATOH1 is required for adult hair cell maintenance unknown
    • Mechanism of ATOH1-independent Pou4f3 maintenance unexplained
  16. 2014 High

    Identification of Huwe1 as the E3 ubiquitin ligase for phosphorylation-dependent ATOH1 degradation, opposed by SHH signaling, resolved the long-sought degradation machinery and explained how SHH sustains ATOH1 in cerebellar progenitors; reciprocal knock-in of Atoh1 and Ptf1a showed these factors are sufficient to switch cerebellar progenitor spatial identity.

    Evidence In vitro degradation assays identifying Huwe1, phosphomutant Atoh1 stabilization, Huwe1 loss-of-function in medulloblastoma; Ptf1a↔Atoh1 knock-in mice

    PMID:24695699 PMID:24960692

    Open questions at the time
    • Specific phosphorylation sites targeted by Huwe1 not fully mapped
    • Whether Huwe1 operates in non-cerebellar contexts unknown
  17. 2015 High

    Epigenetic profiling revealed that the Atoh1 locus transitions through bivalent (H3K4me3/H3K27me3) to active (H3K9ac) to repressive (H3K9me3) chromatin states during hair cell differentiation, and Atoh1/Phox2b co-expressing RTN neurons were shown to be essential for respiratory chemoreflex.

    Evidence µChIP-qPCR on FACS-purified cochlear cells with HDAC inhibitor validation; intersectional genetics with optogenetics and phrenic nerve recording

    PMID:25866925 PMID:26487780

    Open questions at the time
    • Which chromatin remodelers execute these transitions unknown
    • Whether Atoh1 is required for RTN neuron specification or function unclear
  18. 2016 High

    Intestinal ChIP-seq identified over 700 direct ATOH1 targets and established SPDEF as a transcriptional amplifier that requires ATOH1 to access its targets, placing SPDEF downstream in an obligate epistatic relationship.

    Evidence ChIP-seq and RNA-seq with conditional transgenic epistasis in mouse intestine

    PMID:28174757

    Open questions at the time
    • Whether SPDEF physically interacts with ATOH1 on chromatin unresolved
    • Target gene overlap between intestinal and neural contexts not systematically compared
  19. 2018 High

    A phosphomutant knock-in mouse revealed that multisite phosphorylation of ATOH1 governs the balance between secretory differentiation and stem cell self-renewal, and that phosphorylated ATOH1 is required for intestinal regeneration after injury; a Meis1-Pax6-BMP cascade was identified as an upstream pathway triggering Atoh1 degradation in cerebellar GCPs.

    Evidence Atoh1(9S/T-A) knock-in with lineage tracing and colitis model; Meis1 conditional KO with ChIP showing Meis1 binding upstream of Pax6

    PMID:29317485 PMID:30100168

    Open questions at the time
    • Kinases responsible for the nine phospho-sites not fully identified
    • Whether phospho-regulation operates similarly in hair cells unknown
  20. 2021 High

    The discovery that POU4F3 acts as a pioneer factor downstream of ATOH1 to open closed ATOH1 target enhancers resolved how ATOH1 accesses its full target repertoire in hair cells and Merkel cells despite initially limited chromatin accessibility.

    Evidence ATAC-seq and ChIP-seq in hair cell and Merkel cell progenitors with POU4F3 conditional knockout

    PMID:34266958

    Open questions at the time
    • Whether POU4F3 pioneer function operates in other ATOH1-dependent lineages unknown
    • Structural basis of POU4F3 chromatin opening unresolved
  21. 2022 High

    Systematic deletion of three cooperating Atoh1 enhancers (Eh1, Eh2, Eh3) demonstrated that combinatorial enhancer logic, rather than a single autoregulatory element, controls Atoh1 expression levels for proper hair cell development.

    Evidence ATAC-seq, sequential enhancer deletion mouse models, ChIP confirming Atoh1 binding to all three enhancers

    PMID:35925886

    Open questions at the time
    • Whether these enhancers operate similarly in intestine and cerebellum unknown
    • Trans-acting factors specific to each enhancer not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: which kinases phosphorylate ATOH1 at each regulatory site in vivo, how tissue-specific co-factor complexes direct ATOH1 to distinct target sets across lineages, whether the Huwe1-mediated degradation pathway operates outside the cerebellum, and what mechanisms underlie the age-dependent loss of competence for ATOH1-driven hair cell regeneration.
  • Kinase identity for ATOH1 phospho-sites largely unknown
  • Structural basis of ATOH1-E-protein heterodimer target selectivity unresolved
  • Therapeutic potential for hair cell regeneration limited by unknown competence restriction mechanisms

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 10 GO:0140110 transcription regulator activity 9
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-1266738 Developmental Biology 10 R-HSA-162582 Signal Transduction 6 R-HSA-392499 Metabolism of proteins 6
Partners
EYA1HES5HUWE1POU4F3SIX1SOX2TCF3TCF4

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Math1 (ATOH1) is required for the genesis of cochlear and vestibular hair cells; Math1-null mice fail to generate inner ear hair cells, establishing Math1 as necessary for hair cell fate determination. Targeted gene knockout (Math1-null mice), histological analysis Science High 10364557
2000 Overexpression of Math1 in postnatal rat cochlear explants is sufficient to produce extra hair cells from columnar epithelial cells outside the sensory epithelium (greater epithelial ridge), demonstrating Math1 sufficiency for hair cell fate. Transgene overexpression in cochlear explant cultures, immunocytochemistry Nature Neuroscience High 10816314
2001 Loss of Math1 leads to depletion of intestinal goblet, enteroendocrine, and Paneth cells without affecting enterocytes, establishing Math1 as required for secretory cell lineage commitment downstream of a common secretory progenitor. Math1-null mouse analysis, histology, cell-type marker immunostaining Science High 11739954
2000 Math1 autoregulates its own expression through an essential E-box consensus binding site within the conserved Math1 enhancer, and two discrete conserved enhancer sequences within 21 kb flanking the Math1 coding region are sufficient to drive Math1 expression in its normal developmental domains. Transgenic reporter (lacZ) assays, E-box mutagenesis, enhancer deletion analysis Development High 10683172
2001 Math1 null embryos lack D1 interneurons (dorsal commissural interneurons) and the spinocerebellar/cuneocerebellar tracts; Math1 directly governs expression of downstream genes Lh2A, Lh2B, and Barhl1 in the proprioceptive pathway. Math1-null mouse analysis, tract tracing, in situ hybridization Neuron High 11395003
2001 Math1 and Ngn1 exhibit cross-inhibition in dorsal spinal cord progenitors; Math1 expression in dorsal progenitors specifies LH2A/B-expressing dI1 interneurons, while Ngn1 specifies dorsal Lim1/2-expressing interneurons, demonstrating that cross-inhibition between bHLH factors creates discrete progenitor domains. Loss- and gain-of-function experiments in mouse and chick neural tube, immunohistochemistry Neuron High 11502254
2002 Math1 is not required to establish the postmitotic sensory primordium of the organ of Corti, but is specifically required for the selection and/or differentiation of hair cells from within this established primordium; Math1 expression is limited to a subpopulation of cells that differentiate exclusively into hair cells. Math1-null mouse analysis, BrdU labeling, in situ hybridization, cell fate analysis Development High 11973280
2002 Drosophila atonal and mouse Math1 are functionally interchangeable: Math1 expressed in atonal mutant flies rescues chordotonal organ development, and atonal expressed in Math1-null mice fully rescues the Math1 null phenotype, demonstrating deep functional conservation of the proneural activity. Cross-species transgenic rescue experiments Current Biology High 12372255
2003 ATOH1/E47 heterodimers bind to two E-boxes in the proximal promoter of CHRNA1 (nicotinic acetylcholine receptor α1 subunit), directly activating CHRNA1 transcription in inner ear hair cells, identifying CHRNA1 as a direct transcriptional target of ATOH1. Electrophoretic mobility-shift assays (EMSA), supershift assays, reporter assays Journal of Neurochemistry High 17961150
2003 Zic1 represses Math1 expression by binding a conserved site within the Math1 enhancer and blocking Math1 autoregulatory activity; Zic1 overexpression in chick neural tubes represses both endogenous Cath1 expression and Math1 enhancer-driven reporter activity. Transgenic reporter assays, in vivo chick neural tube electroporation, luciferase reporter assays Development High 12642498
2004 Math1 functions as a transcriptional activator; distinct domains within the bHLH motif are required for different functions: helix 2 of Math1 is required for neuronal subtype specification (dI1 interneurons), while helix 1 of Mash1 (not Math1) is required for neuronal differentiation activity. Domain-swap mutagenesis, chick neural tube electroporation, gain-of-function analysis Development High 14993186
2004 Math1 controls cerebellar granule cell differentiation by regulating multiple components of the Notch signaling pathway including Notch4, Dll1, and Hes5; Hes5 physically binds MATH1 (establishing a negative regulatory feedback loop), and Math1 participates in both positive autoregulatory and negative feedback loops. Primary CGC cultures from Math1/lacZ knockout mice, co-immunoprecipitation (Hes5 binding), in vitro differentiation assays Development Medium 14757642
2005 Gfi1 functions downstream of Math1 in intestinal secretory lineage differentiation; Gfi1-null mice lack Paneth cells and have fewer goblet cells with supernumerary enteroendocrine cells, placing Gfi1 downstream of Math1 to select goblet/Paneth versus enteroendocrine progenitors. Gfi1-null mouse analysis, genetic epistasis, gene expression analysis Genes & Development High 16230531
2005 Math1 directly regulates the commissural neuron identity gene Mbh1 by binding to an E-box in the Mbh1 enhancer; misexpression of Math1 induces ectopic Mbh1 expression, and Mbh1 is lost in Math1 knockout mice. Chromatin immunoprecipitation (ChIP), transgenic enhancer analysis, Math1 KO, misexpression in chick spinal cord Development High 15788459
2006 GSK3β mediates proteasome-dependent degradation of Hath1 (human ATOH1) protein in colon cancer cells in a reciprocal manner with β-catenin: Wnt signaling switches GSK3β substrate targeting between Hath1 and β-catenin. FLAG-tagged Hath1 expression in human cell lines, GSK3β inhibitor treatment, proteasome inhibitor assays Gastroenterology Medium 17241872
2007 The E-protein Tcf4 physically interacts with Math1 and is specifically required for Math1-dependent pontine nucleus development; Tcf4-null mice show selective pontine nucleus deficits without affecting other rhombic lip-derived nuclei, demonstrating that specific E-protein partners confer specificity to proneural factor function. Protein-protein interaction (pulldown/co-IP), Tcf4-null mouse analysis, immunohistochemistry PNAS High 17878293
2007 Math1 is epistatic to Notch (RBP-Jκ) signaling in intestinal secretory cell differentiation and crypt cell proliferation; loss of Math1 in RBP-Jκ conditional mutants blocks the conversion of progenitors to secretory cells and restores crypt proliferation, establishing that all intestinal Notch effects channel through Math1. Compound conditional mouse mutants (RBP-Jκ/Math1 double knockout), genetic epistasis Journal of Biological Chemistry High 21282114
2008 BMP2/4 promote rapid proteasome-mediated degradation of Math1 (Atoh1) protein in cerebellar granule neuron progenitors; ectopic Atoh1 expression cancels BMP-mediated inhibition of proliferation, identifying proteasomal degradation as a mechanism by which BMPs suppress Math1 and medulloblastoma. Proteasome inhibitor assays, ectopic Atoh1 expression in GNPs and medulloblastoma cells, in vivo transplantation Genes & Development High 18347090
2008 Proteasomal degradation of Hath1 mediated by the Wnt-GSK3 axis maintains the undifferentiated state of colon cancer; stabilization of Hath1 protein by GSK3 inhibitor or constitutive expression of mutant Hath1 increases MUC2 expression (goblet cell differentiation marker). GSK3 inhibitor treatment, mutant Hath1 expression in colon cancer cells, MUC2 reporter assays Biochemical and Biophysical Research Communications Medium 18275842
2009 Beta-catenin (canonical Wnt pathway) upregulates Atoh1 expression by binding to two Tcf-Lef sites in the 3' enhancer of the Atoh1 gene; mutation of either site reduces reporter gene expression, and Tcf-Lef co-activators form a complex with beta-catenin at these sites. Chromatin immunoprecipitation (ChIP), siRNA knockdown, Tcf-Lef site mutagenesis, reporter assays Journal of Biological Chemistry High 19864427
2010 Conversion of intestinal stem cells into goblet cells upon inhibition of Notch signaling requires Math1; Math1-deficient intestinal stem cells are refractory to Notch inhibitor-induced goblet cell conversion, establishing Math1 as genetically downstream of Notch in secretory cell fate commitment. Genetic epistasis with γ-secretase inhibitors in Math1-deficient mice, histology Nature Communications High 20975679
2011 Atoh1 directly regulates over 600 target genes in the postnatal cerebellum by binding to a 10-nucleotide motif (AtEAM), including genes involved in migration, cell adhesion, and metabolism, as determined by genome-wide ChIP-seq. ChIP-seq, motif analysis, in vivo targetome characterization PNAS High 21300888
2011 Atoh1 in vivo directly regulates neuronal subtype-specific target genes (Klf7, Rab15, Rassf4, Selm, Smad7) in dorsal spinal cord dI1 interneurons, with Atoh1-responsive enhancers identified by ChIP-seq. Microarray of sorted bHLH-expressing populations, ChIP-seq, enhancer reporter assays in transgenic mice Journal of Neuroscience High 21795538
2011 ATOH1 is essential for tuft cell differentiation in the intestinal epithelium, while Neurog3, SOX9, GFI1, and SPDEF are dispensable for tuft cell development, distinguishing the tuft cell lineage as a distinct ATOH1-dependent secretory cell type. Conditional knockout mice for multiple transcription factors, lineage tracing, immunohistochemistry Journal of Cell Biology High 21383077
2012 Eya1/Six1 activate Atoh1 transcription synergistically with Sox2 via direct binding to conserved Sox- and Six-binding sites in Atoh1 enhancers; the three proteins physically interact and coexpression of Eya1/Six1 in mouse cochlear explants induces hair cell fate by activating Atoh1-dependent and Atoh1-independent pathways. Luciferase reporter assays with enhancer mutagenesis, co-immunoprecipitation, cochlear explant overexpression Developmental Cell High 22340499
2012 Atoh1 induces ectopic sensory patches in the postnatal cochlea through Notch signaling to form cellular mosaics, and also activates proliferation within the normally postmitotic cochlear epithelium; competency for hair cell differentiation is cell-type specific and progressively restricted with age. Conditional Atoh1 overexpression mouse model, Notch signaling manipulation, BrdU proliferation assays, electrophysiology Journal of Neuroscience High 22573692
2013 Continued Atoh1 expression is required for hair cell survival and maintenance of downstream transcription factors Barhl1 and Gfi1; conditional deletion of Atoh1 at E15.5 leads to death of all cochlear hair cells, while later deletion causes progressive apical hair cell loss with stereocilia abnormalities. Maintained expression of Pou4f3 and several HC markers is Atoh1-independent. Conditional Atoh1 deletion at multiple embryonic timepoints, immunostaining for downstream TFs Developmental Biology High 23796904
2014 SHH signaling protects Atoh1 from phosphorylation-dependent proteasomal degradation by the E3 ubiquitin ligase Huwe1; SHH prevents Huwe1-mediated Atoh1 degradation, maintaining Atoh1 levels in cerebellar granule neuron progenitors and contributing to a positive autoregulatory loop. In vitro degradation assays, Huwe1 loss-of-function in mouse medulloblastoma, phosphomutant Atoh1 expression Developmental Cell High 24960692
2015 Retrotrapezoid nucleus (RTN) neurons defined by co-expression of Atoh1 and Phox2b are necessary components of the respiratory chemoreflex circuit; abrogating Atoh1 or Phox2b expression or glutamatergic transmission in these neurons abolishes the phrenic nerve response to low pH. Intersectional genetic strategies, optogenetics, phrenic nerve recording, behavioral assays eLife High 25866925
2015 Epigenetic regulation of the Atoh1 locus involves dynamic histone modifications (H3K4me3/H3K27me3 bivalent poised state in progenitors transitioning to active H3K9ac marks in hair cells, then repressive H3K9me3); inhibition of histone acetylation blocks Atoh1 upregulation and hair cell differentiation in embryonic cochlear explants. µChIP-qPCR on FACS-purified cochlear cells, histone modification profiling, HDAC inhibitor experiments Development High 26487780
2016 ATOH1 directly regulates over 700 target genes in the adult intestine (identified by ChIP-seq), and SPDEF acts as a transcriptional co-regulator that amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes (epistasis: ATOH1 upstream of SPDEF). ChIP-seq, RNA-seq, conditional transgenic epistasis experiments in mice Cellular and Molecular Gastroenterology and Hepatology High 28174757
2017 ErbB3 negatively regulates Paneth cell differentiation through PI3K-mediated suppression of Atoh1 protein levels; ErbB3 knockout increases Atoh1 levels and Paneth cell numbers, and ErbB3 activation suppresses ATOH1 and the Paneth cell marker LYZ in a PI3K-dependent manner. Intestinal epithelial ErbB3 knockout mice, PI3K inhibitor assays in HT29 cells, immunostaining Cell Death and Differentiation Medium 28304405
2018 Phosphorylation of ATOH1 at multiple serine/threonine sites regulates the balance between secretory progenitor commitment and stem cell self-renewal; a phosphomutant Atoh1(9S/T-A) promotes secretory differentiation and inhibits progenitor contribution to self-renewal, and phospho-ATOH1 is required for robust regeneration after colitis. Phosphomutant knock-in mouse (Atoh1(9S/T-A)CreERT2), lineage tracing, colitis model Cell Stem Cell High 30100168
2021 ATOH1 is unable to access much of its target enhancer network in hair cell or Merkel cell progenitors when it first appears; ATOH1 first stimulates expression of POU4F3, which then acts as a pioneer factor to open closed ATOH1 enhancers via a feed-forward mechanism, enabling hair cell and Merkel cell differentiation. ATAC-seq, ChIP-seq, conditional knockout of POU4F3 in hair cell and Merkel cell progenitors, chromatin accessibility profiling PNAS High 34266958
2022 Three distinct Atoh1 enhancers (Eh1, Eh2, Eh3) cooperate for hair cell development; Eh2 deletion alone impairs hair cell development, concurrent deletion of Eh1+Eh2 or all three results in near-complete absence of hair cells. Atoh1 binds all three enhancers, consistent with its autoregulatory function. ATAC-seq, enhancer deletion mouse models, ChIP showing Atoh1 binding to all three enhancers PNAS High 35925886
2008 Math1 directly regulates Bar-class homeobox genes Mbh1 and Mbh2 in cerebellar granule cells (CGCs); misexpression of Math1 ectopically induces Mbh1/Mbh2, and Math1 knockdown represses them; ChIP assays confirmed direct Math1 binding at the Mbh gene loci. Dominant-negative Mbh proteins disrupt CGC differentiation. ChIP, in vivo electroporation in mouse cerebellum, dominant-negative constructs Developmental Biology High 18723012
2008 Prox1 represses Atoh1 and Gfi1 expression in inner ear hair cells; adenoviral Prox1 transduction into hair cells strongly represses Atoh1 and Gfi1 transcriptional activity (confirmed by luciferase assays showing Prox1 represses Gfi1 independently of Atoh1), and causes degeneration of outer hair cells. Adenoviral transduction of cochlear explants, luciferase reporter assays, immunostaining Developmental Biology Medium 18652815
2006 HATH1 (human ATOH1) directly transactivates the MUC2 promoter via putative HATH1-binding sites; mutation of these sites significantly inhibits MUC2 promoter/reporter activity, establishing MUC2 as a direct ATOH1 transcriptional target. MUC2 promoter/reporter transactivation assays with binding site mutagenesis Clinical Cancer Research Medium 17000673
2014 Ptf1a and Atoh1 are sufficient to specify spatial identity of cerebellar neuron progenitors: ectopic Atoh1 expression in the ventricular zone (VZ) redirects VZ cells to produce glutamatergic neurons, while ectopic Ptf1a in the rhombic lip (RL) produces GABAergic populations; Ptf1a and Atoh1 mutually negatively regulate each other's expression. Knock-in mouse lines (Ptf1a(Atoh1) and Atoh1(Ptf1a)), in utero electroporation, BrdU birthdating Journal of Neuroscience High 24695699
2004 PC3 (Tis21/BTG2) acts upstream of Math1 in cerebellar neurogenesis: PC3 overexpression increases Math1 expression and stimulates Math1 promoter activity in postmitotic granule cells; Math1 expression is unaffected in the cerebellar primordium of PC3 transgenic mice's Math1 null background, confirming PC3 is upstream of Math1. PC3 transgenic mice, adenoviral PC3 expression, Math1 promoter reporter assays, in vitro granule cell cultures Journal of Neuroscience Medium 15056715
2018 Meis1 regulates Atoh1 degradation in cerebellar granule cell precursors (GCPs) via a Meis1-Pax6-BMP signaling cascade: Meis1 binds upstream of Pax6 to enhance its transcription, the Meis1-Pax6 cascade upregulates Smad protein expression to activate BMP signaling, and BMP signaling then induces Atoh1 degradation in the inner EGL. Meis1 conditional KO in GC lineage, Smad phosphorylation analysis, ChIP showing Meis1 binding to Pax6, cerebellar slice electroporation Journal of Neuroscience Medium 29317485

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Math1: an essential gene for the generation of inner ear hair cells. Science (New York, N.Y.) 895 10364557
2001 Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science (New York, N.Y.) 757 11739954
2000 Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nature neuroscience 619 10816314
2002 The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development (Cambridge, England) 433 11973280
2011 Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. The Journal of cell biology 317 21383077
2012 Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proceedings of the National Academy of Sciences of the United States of America 259 22586121
2003 Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene expression patterns : GEP 258 12915300
2000 Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development (Cambridge, England) 257 10683172
2005 Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes & development 256 16230531
2007 Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 250 17570220
1998 Progenitors of dorsal commissural interneurons are defined by MATH1 expression. Development (Cambridge, England) 245 9449674
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2012 Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Developmental cell 193 22340499
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2007 Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development (Cambridge, England) 170 18039969
2007 The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proceedings of the National Academy of Sciences of the United States of America 166 17878293
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2006 Zebrafish atoh1 genes: classic proneural activity in the inner ear and regulation by Fgf and Notch. Development (Cambridge, England) 153 17166920
2011 In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar development. Proceedings of the National Academy of Sciences of the United States of America 125 21300888
2008 Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes & development 124 18347090
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2009 Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proceedings of the National Academy of Sciences of the United States of America 109 20080794
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2004 Math1 controls cerebellar granule cell differentiation by regulating multiple components of the Notch signaling pathway. Development (Cambridge, England) 88 14757642
1999 Ectopic expression of the bHLH gene Math1 disturbs neural development. The European journal of neuroscience 88 10383648
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2015 The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO₂. eLife 81 25866925
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2011 Genetic evidence that intestinal Notch functions vary regionally and operate through a common mechanism of Math1 repression. The Journal of biological chemistry 76 21282114
2002 Drosophila atonal fully rescues the phenotype of Math1 null mice: new functions evolve in new cellular contexts. Current biology : CB 76 12372255
2006 Reciprocal targeting of Hath1 and beta-catenin by Wnt glycogen synthase kinase 3beta in human colon cancer. Gastroenterology 75 17241872
2004 Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 15056715
2016 Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine. Cellular and molecular gastroenterology and hepatology 74 28174757
2009 Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation. Cell and tissue research 74 19609565
2013 Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Developmental biology 73 23796904
2014 Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. PloS one 71 25036727
2014 Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 24695699
2014 Shh signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors. Developmental cell 69 24960692
2003 Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription factors Mash1 and Math1. Journal of neuroscience research 69 12584723
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2021 POU4F3 pioneer activity enables ATOH1 to drive diverse mechanoreceptor differentiation through a feed-forward epigenetic mechanism. Proceedings of the National Academy of Sciences of the United States of America 55 34266958
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2015 Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea. Development (Cambridge, England) 54 26487780
2021 Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells. eLife 53 34477109
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2007 Conserved regulation of Math5 and Math1 revealed by Math5-GFP transgenes. Molecular and cellular neurosciences 29 17900924
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2008 Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer. Biochemical and biophysical research communications 27 18275842
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2013 In vivo delivery of Atoh1 gene to rat cochlea using a dendrimer-based nanocarrier. Journal of biomedical nanotechnology 26 24015503
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