Atoh1 drives the heterogeneity of the pontine nuclei neurons and promotes their differentiation
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ABSTRACT:
PROVIDER: PRJNA929454 | ENA |
REPOSITORIES: ENA
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Project description:Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex and the cerebellum to refine skilled motor functions. Prior studies have shown that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss-of-function of Atoh1 in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell-state-specific functions of Atoh1 during PN development and discovered that Atoh1 regulates cell cycle exit, differentiation, migration, and survival of the PN neurons. Importantly, our data revealed six previously not known PN subtypes that are molecularly and spatially distinct. Interestingly, we found the PN subtypes exhibit differential vulnerability to partial loss of Atoh1 function, providing insights into the prominence of PN phenotypes in patients with ATOH1 missense mutations.
2023-07-06 | GSE224031 | GEO
Project description:Cortico-ponto-cerebellar topographic circuit formation requires patterned expression of chemotropically active molecules as well as differential expression of axon guidance molecules within the pontine nuclei. We carried out RNA-sequencing experiments on different sets of genetically identified or manipulated pontine nuclei neurons followed by comparative transcriptome analysis to identify genes which are potentially involved in controlling PN circuit formation and are regulated by Hoxa5.
2017-09-02 | GSE72710 | GEO
Project description:During brain development, layer 5 neurons distributed across most areas of the neocortex innervate the pontine nuclei (basilar pons) by the initiation and extension of collateral branches interstitially along their corticospinally extending axons. We used microarrays to compare gene expression profiles of pontine nucleus when axon collaterals towards the pontine nucleus start to extend (embryonic day 17.5 (E17.5) to postnatal day 1 (P1)), and/or throughout the development (E17.5-P14) in order to understand genetic programs that regulate axon collaterals formation.
2020-11-30 | GSE140760 | GEO
Project description:Proneural transcription factors set up the molecular cascade to orchestrate neuronal diversity. One such transcription factor, Atoh1, gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although the neurons that arise from the Atoh1-lineage have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA-sequencing and ATOH1 DNA binding in Atoh1-lineage neurons of the developing mouse hindbrain. This high-resolution dataset revealed new markers for specific brainstem nuclei and demonstrated transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable proliferating unipolar brush cell progenitor in the mouse Atoh1-lineage that was described in humans as the origin of one medulloblastoma subtype. Collectively, our data reveal unprecedented insight into the developing mouse hindbrain and provide markers for functional assessment of less studied neuronal populations.
2024-06-23 | GSE233964 | GEO
Project description:Proneural transcription factors set up the molecular cascade to orchestrate neuronal diversity. One such transcription factor, Atoh1, gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although the neurons that arise from the Atoh1-lineage have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA-sequencing and ATOH1 DNA binding in Atoh1-lineage neurons of the developing mouse hindbrain. This high-resolution dataset revealed new markers for specific brainstem nuclei and demonstrated transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable proliferating unipolar brush cell progenitor in the mouse Atoh1-lineage that was previously described as the origin of one medulloblastoma subtype. Collectively, our data reveal unprecedented insight into the developing mouse hindbrain and provide markers for functional assessment of less studied neuronal populations.
2024-06-23 | GSE233856 | GEO
Project description:To investigate the function of Atoh1 in colon cancer cells. We have employed whole genome microarray expression profiling as a discovery platform to iedntify the gene expression induced by Atoh1 in colon cancer cells. Mutated Atoh1 (5SA-Atoh1) replaced 5 serine residues to Alanin for the protein stabilization were expressed in human colon cancer cellline; DLD1 cells. Triplicated RNAs were generated from GFP expressing DLD1 cells and 5SA-Atoh1 expressing DLD1 cell, respectively.
2012-04-10 | E-GEOD-37143 | biostudies-arrayexpress
Project description:A relatively small number of proneural transcription factors specify a multitude of neural progenitor populations in the developing mammalian brain. Despite their importance, little is known about their targets, cellular processes they regulate, or what genomic sites they occupy in vivo. We used an integrated experimental and computational approach, combining RNA-seq, Histone-seq, and Atoh1 ChIP-seq in cerebellar tissue, to identify over 600 targets of Atoh1, an important developmental transcription factor. We validated 10% of these targets and found that Atoh1 directly regulates genes involved not only in early proliferation but also later differentiation, migration, cell adhesion, metabolism, and cytoskeletal organization by recognizing a novel 10 nucleotide Atoh1 E-Box associated motif (AtEAM). This Atoh1 “targetome” is not only a resource for studies aimed at understanding the molecular mechanisms involved in cerebellar development, but our integrated approach provides a framework for future in vivo studies of transcription factors and their targetomes. Examination of RNA-seq WT and null expression data (2 reps each), 2 different histone modifications (2 rep each) and IgG control, and Atoh1 DNA-binding (2 reps each) and control in the developing cerebellum
2011-02-08 | E-GEOD-22111 | biostudies-arrayexpress
Project description:The functional unit of the inner ear consists of hair cells (HCs) and neurons in the inner ear. Both genes are induced early in development, but Atoh1 expression is counteracted by Neurog1. As a result, HC development is prevented during neurogenesis. This work aimed at understanding the molecular basis of this interaction. Atoh1 regulation depends on a 3’Atoh1-enhancer that is the site for Atoh1 autoregulation. This enhancer recapitulates Atoh1 expression in the embryo and contains putative binding sites for several transcription factors, including basic helix-loop-helix (bHLH) factors like Atoh1, Neurog1 and Hes/Hey repressors. Reporter assays on chick embryos and P19 cells show that Neurog1 hampers the autoactivation of Atoh1, the effect being cell autonomous and independent on Notch activity. ATAC-seq analysis shows that the region B of the 3’Atoh1-enhancer is accessible during development and sufficient for both activation and repression. Neurog1 requires the regions flanking the class A E-box bound by Atoh1 to show its repressor effect. However, Neurog1 does not require binding to DNA for Atoh1 repression and prevention of HC formation, but the dimerization domains Helix-1 and Helix-2. The repression of Atoh1 by Neurog1 does not involve the direct interaction between Atoh1 and Neurog1, but rather an indirect effect on the levels of Atoh1 protein. The results suggest that Neurog1 induces the acceleration of Atoh1 mRNA degradation and the consequent reduction of protein levels. Such a mechanism dissociates the prevention of Atoh1 expression in neuro-sensory progenitors from the unfolding of the neurogenic program.
2017-11-09 | GSE102649 | GEO
Project description:Neural basic helix-loop-helix (bHLH) transcription factors are important for the differentiation and cell type specification of neurons. They are thought to share direct downstream targets in their common role as neuronal differentiation factors, but have distinct targets with respect to their cell type specific roles. Little is known about distinct cell-type specific bHLH targets as previous work did not distinguish these from common targets. Based on previous genetic evidence, we hypothesize that bHLH transcription factors have unique targets for their function in regulating neuronal sub-type specification. Atoh1 (Math1) is a bHLH transcription factor that specifies different cell types of the proprioceptive pathway in mammals such as the dorsal interneuron 1 population of the developing neural tube. Using microarray analyses of neighboring specific bHLH sorted populations from developing mouse neural tubes, we determine transcripts unique to the Atoh1-derived population and not those common to bHLH transcription factors in related neural progenitor populations. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments of native tissue followed by enhancer reporter analyses identified five direct cell-type specific targets of Atoh1 in vivo: Klf7, Rab15, Rassf4, Selm, and Smad7, along with their Atoh1-responsive enhancers. These Atoh1 targets were found from native tissue in the appropriate developmental context and have diverse functions that range from transcription factors to regulators of endocytosis and signaling pathways. Only Rab15 and Selm are expressed across several different Atoh1-specified cell types including external granule cells (EGL) in the developing cerebellum, hair cells of the inner ear, and Merkel cells, demonstrating that even within Atoh1 lineages, not all Atoh1 specific targets are shared. Our work establishes on a molecular level that the neuronal differentiation bHLH transcription factors also have distinct targets for their roles in neuronal sub-type specification. From this work, we can begin to address how bHLH transcription factors are able to specify unique cell types and initiate programs that organize neuronal diversity. Gene expression analysis: Two samples, Atoh1-GFP and dNeurog1-GFP, were analyzed. Two biological replicates of each. Atoh1-GFP transgenics are mice with GFP inserted into a BAC that drives GFP to the Atoh1-derived population of the developing neural tube marking the dorsal interneuron 1 population (Raft et al. Development 2007). dNeurog1-GFP transgenics are mice with a Neurog1 enhancer that drives GFP to the dorsal part of the developing neural tube marking the dorsal interneuron 2 population (Nakada et al. Dev Bio 2004). Chip-seq analysis: Series GSE22111
2011-07-26 | E-GEOD-23089 | biostudies-arrayexpress
Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator- Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.
2023-03-10 | PXD030212 | Pride