Olfactory receptor accessory proteins play crucial roles in receptor gene choice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE87694 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA345584
REPOSITORIES: GEO
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Project description:In the mouse, more than 1,100 odorant receptors (ORs) are expressed in a monogenic and monoallelic fashion, referred to as singular gene expression. Here we utilize multimers of a naturally occurring 21bp enhancer (x21) and radically increase the number of olfactory sensory neurons (OSNs) choosing an OR transgene that is normally expressed by Class II cell types. Surprisingly, hundreds of ORs derived from Class I, Class II and TAAR cell types have reduced expression and are replaced by the OR transgene expression leading to novel glomeruli formed in three segregating domains of glomeruli on the olfactory bulb: DI (Class I), DII (Class II), and DIII (TAAR). The reduction of expression across distinct cell types that were thought to have distinct mechanisms of singular gene choice in favor of the expression of the x21-OR transgene argues that a common mechanism of singular gene choice is present for all OR-expressing OSNs.
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Project description:In the mouse, more than 1,100 odorant receptors (ORs) are expressed in a monogenic and monoallelic fashion, referred to as singular gene expression. Using a 21bp singular-choice enhancer (x21), we radically increase representation of olfactory sensory neurons (OSNs) choosing a 5×21 enhanced OR transgene, but not overexpression of its mRNA on a per cell basis. RNA-sequencing and differential expression analysis identified 425 differentially expressed genes (DEGs). ORs make up 86% of all DEGs, of which 325 have decreased representation and 40 have increased representation. Underrepresented ORs include Class I, Class II and TAAR genes and within each of their respective olfactory bulb domains: DI, DII, and DIII (TAAR) we committedly observe multiple homogeneous glomeruli with an OR1A1-identity. The underrepresentation of endogenous, class-specific ORs across evolutionarily distinct cell types in favor of the expression of the 5×21-OR1A1 transgene argues that a common mechanism of singular gene choice is present for all OR-expressing OSNs
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| S-EPMC5362263 | biostudies-literature
Project description:Although topographical maps organize many peripheral sensory systems, mouse olfactory sensory neurons (OSNs) are thought to randomly choose which one of ~1,100 possible olfactory receptors (ORs) to express, with spatial organization in the olfactory epithelium limited to a handful of broad anatomical zones that modestly restrict OR choice. Here we reveal that each OR is instead expressed at a unique mean dorsoventral position, thereby instantiating a stereotyped receptor map in the olfactory epithelium. OSN dorsoventral identities are encoded by a coherent gene expression program, which includes key transcription factors and axon guidance molecules; use of this program reflects a dorsoventral gradient in retinoic acid signaling, translates each physical location into a spatially appropriate distribution of potential OR choices, and aligns receptor maps in the nose and brain. Spatial order in the olfactory system, therefore, arises from a continuously varying transcriptional code that precisely organizes the many discrete channels responsible for smell.
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Project description:The cell surface metalloprotease ADAM17 and its binding partners iRhom2 and iRhom1 modulate cell-cell interactions by mediating the release of membrane proteins such as TNFa and EGFR-ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of over a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of OR2AT4 by its agonist sandalore in keratinocytes, where this receptor is ectopically expressed, leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.
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Project description:Olfactory sensory neurons (OSNs) transform the stochastic choice of one out of >1000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons, and the specificity of their projections. Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER signaling patterns to the transcriptional regulation of axon guidance and cell adhesion genes, instructing targeting precision. Our results extend the known functions of the UPR from a quality control pathway that protects cells from misfolded proteins, to a sensor of cellular identity that interprets physiological states to direct axon wiring.
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Project description:Diverse epigenetic regulatory mechanisms ensure and regulate cellular diversity. Among 18 others, the histone 3 lysine 9 me3 (H3K9me3) post translational modification participates 19 in silencing lineage-inappropriate genes. H3K9me3 restricts access of transcription factors 20 and other regulatory proteins to genes that control cell fate. Mouse olfactory sensory neu- 21 rons (OSN) select to express one olfactory receptor (OR) gene out of 2,600 possibilities. 22 This monoallelic and stochastic OR choice happens as OSNs differentiate and undergo 23 dramatic changes in nuclear architecture. OR genes from different chromosomes converge 24 into specialized nuclear bodies and chromatin compartments, as H3K9me3 and chromatin 25 binding proteins including heterochromatin protein 1 (HP1) are incorporated. In this 26 work, we have uncovered an unexpected role for HP1b in OR choice and neuronal iden- 27 tity that cannot be rescued by HP1a in vivo. With the use of a conditional knock-in mouse 28 model that replaces HP1b for HP1a, we observe changes in H3K9me3 levels and DNA 29 accessibility over OR gene clusters. These changes alter the expression paTerns that par- 30 tition the mouse olfactory epithelium into five OR expression zones, which results in a 31 reduced OR repertoire leading to a loss of olfactory sensory neuron diversity. We propose 32 that HP1b modulates the competition of OR-promoters for enhancers to promote receptor 33 diversity, by establishing repression gradients in a zonal fashion.
2026-04-22 | GSE324728 | GEO
Project description:Diverse epigenetic regulatory mechanisms ensure and regulate cellular diversity. Among others, the histone 3 lysine 9 me3 (H3K9me3) post translational modification participates in silencing lineage-inappropriate genes. H3K9me3 restricts access of transcription factors and other regulatory proteins to genes that control cell fate. Mouse olfactory sensory neurons (OSN) select to express one olfactory receptor (OR) gene out of 2,600 possibilities. This monoallelic and stochastic OR choice happens as OSNs differentiate and undergo dramatic changes in nuclear architecture. OR genes from different chromosomes converge into specialized nuclear bodies and chromatin compartments, as H3K9me3 and chromatin binding proteins including heterochromatin protein 1 (HP1) are incorporated. In this work, we have uncovered an unexpected role for HP1b in OR choice and neuronal identity that cannot be rescued by HP1a in vivo. With the use of a conditional knock-in mouse model that replaces HP1b for HP1a, we observe changes in H3K9me3 levels and DNA accessibility over OR gene clusters. These changes alter the expression paTerns that partition the mouse olfactory epithelium into five OR expression zones, which results in a reduced OR repertoire leading to a loss of olfactory sensory neuron diversity. We propose that HP1b modulates the competition of OR-promoters for enhancers to promote receptor diversity, by establishing repression gradients in a zonal fashion.
2026-04-22 | GSE325634 | GEO
Project description:Diverse epigenetic regulatory mechanisms ensure and regulate cellular diversity. Among others, the histone 3 lysine 9 me3 (H3K9me3) post translational modification participates in silencing lineage-inappropriate genes. H3K9me3 restricts access of transcription factors and other regulatory proteins to genes that control cell fate. Mouse olfactory sensory neurons (OSN) select to express one olfactory receptor (OR) gene out of 2,600 possibilities. This monoallelic and stochastic OR choice happens as OSNs differentiate and undergo dramatic changes in nuclear architecture. OR genes from different chromosomes converge into specialized nuclear bodies and chromatin compartments, as H3K9me3 and chromatin binding proteins including heterochromatin protein 1 (HP1) are incorporated. In this work, we have uncovered an unexpected role for HP1b in OR choice and neuronal identity that cannot be rescued by HP1a in vivo. With the use of a conditional knock-in mouse model that replaces HP1b for HP1a, we observe changes in H3K9me3 levels and DNA accessibility over OR gene clusters. These changes alter the expression paTerns that partition the mouse olfactory epithelium into five OR expression zones, which results in a reduced OR repertoire leading to a loss of olfactory sensory neuron diversity. We propose that HP1b modulates the competition of OR-promoters for enhancers to promote receptor diversity, by establishing repression gradients in a zonal fashion.
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Project description:Olfaction plays important roles in food and mate choice, and also in the avoidance of predators, making it a vital sensory modality for preservation and reproduction. In the vertebrates, olfactory receptors are thought to localise on multiple cilia elaborated on the dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause loss of the sense of smell, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a fork head-domain containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium formation. In keeping with the immotile nature of the olfactory cilia, we observed that ciliary motility genes that are the targets of Foxj1 in motile ciliated cells, are repressed in the OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odour-evoked signal transduction. In line with these requirements, response to bile acid, an odour detected by OMP-positive OSNs, was significantly diminished in the foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of the immotile olfactory cilia and for the development of the OSNs themselves.
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