Functional Interrogation of an Odorant Receptor Locus Reveals Multiple Axes of Transcriptional Regulation

Fleischmann, Alexander; Abdus-Saboor, Ishmail; Sayed, Atef K.; Shykind, Benjamin

doi:10.1371/journal.pbio.1001568

Cited by 24 publications

(36 citation statements)

References 45 publications

(115 reference statements)

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“…It is possible that during this critical period the repressive chromatin compartments are not yet stably established, allowing for switching until a functional OR gene is expressed and OR gene choice is stabilized. In agreement with this is the recent observation that biallelic expression of an OR gene is possible but very infrequent and occurs predominantly in younger neurons (44).…”

Section: Discussionsupporting

confidence: 85%

“…The fact that they are present also in immature olfactory neurons, and that OR gene choice probably occurs during terminal differentiation to neurons from neuronal precursors or in immature olfactory neurons, suggests that they are formed before or concomitant with OR gene expression. One intriguing possibility is that they could be formed as a result of the feedback signal that is elicited by an expressed OR gene to prevent the expression of additional OR genes, and thereby contribute to the stability of OR gene choice (44). Alternatively, we cannot yet exclude the possibility that repression of the OR gene alleles by facultative heterochromatin is established before an OR gene is chosen for expression, and removed during neuronal development, as it has been shown for several neural lineage genes (45).…”

Section: Discussionmentioning

confidence: 99%

“…These enhancers, would now select an OR gene allele from this limited pool of available OR genes. Alternatively, an OR gene allele would be stochastically and limitedly selected from the pool of the 1,000 unrepressed, available OR gene alleles, with the help of one of the enhancers (44). The expression of this allele would lead to a feedback regulation that would cause the formation of facultative heterochromatin in the additional OR genes.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear compartmentalization of odorant receptor genes

Armelin‐Correa

Gutiyama

Brandt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Odorants are detected by odorant receptors, which are located on olfactory sensory neurons of the nose. Each olfactory sensory neuron expresses one single odorant receptor gene allele from a large family of odorant receptor genes. To gain insight into the mechanisms underlying this monogenic and monoallelic expression, we examined the 3D nuclear organization of olfactory sensory neurons and determined the positions of homologous odorant receptor gene alleles in relation to different nuclear compartments. Our results show that olfactory neurons exhibit a singular nuclear architecture that is characterized by a large centrally localized constitutive heterochromatin block and by the presence of prominent facultative heterochromatin domains that are localized around this constitutive heterochromatin block. We also found that the two homologous alleles of a given odorant receptor gene are frequently segregated to separate compartments in the nucleus, with one of the alleles localized to the constitutive heterochromatin block and the other one localized to the more plastic facultative heterochromatin, or next to it. Our findings suggest that this nuclear compartmentalization may play a critical role in the expression of odorant receptor genes.H3K27me3 | chromatin | OR gene choice

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nuclear compartmentalization of odorant receptor genes

Armelin‐Correa

Gutiyama

Brandt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We and others have used the OMP promoter to force the expression of OR genes (19)(20)(21)(22)(23)(24) as well as to knock out genes via Cre-recombinase (25)(26)(27). However, our current results show that OMP is expressed, at the earliest, 48 h after OR expression is initiated and after axons have reached the OB and drawn proximal to the point of glomerular convergence.…”

Section: Discussioncontrasting

confidence: 60%

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

Rodriguez‐Gil

Bartel

Jaspers

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli.olfactory epithelium | axon guidance | tamoxifen | olfactory marker protein | Ascl1 I n the mouse olfactory system, olfactory sensory neurons (OSNs) extend their axons from the olfactory epithelium (OE) to the olfactory bulb (OB), where they converge to form glomeruli. Each OSN expresses only 1 of ∼2,400 candidate odorant receptor (OR) alleles. OSNs expressing the same OR can be widely dispersed in the OE, yet their axons converge in only two to three molecularly specific glomeruli of a possible 3,700 (1). It was first recognized almost 20 y ago that substituting an OR-coding region with that of a different OR resulted in the glomerular convergence of axons at an ectopic location relative to that of the native ORs (2). This led to the suggestion that ORs have an instructive role in the extension and glomerular coalescence of OSN axons, most likely mediated by homophilic fasciculation (3-5).Postnatal OSNs are derived from self-renewing precursors located proximal to the deep basal lamina of the OE (6). Following the division of globose basal stem cells, OSN neuroblasts transiently express Achaete-scute homolog 1 (Ascl1) followed by two phases of differentiation (6-8). Initially, they express growthassociated protein-43 (GAP-43), a marker of immature cells. Subsequently, the OSNs down-regulate GAP-43 and express olfactory marker protein (OMP), a universal marker of mature OSNs.Although there is a consensus on the involvement of ORs in OSN axon glomerular convergence, when ORs exert that influence following basal cell division or axon extension is not known. Moreover, the developmental progression of GAP-43 to OMP, as a measure of OSN differentiation and maturation, or of adenylate cyclase 3 (AC3), a downstream signaling molecule also implicated in axon extension, has not been considered in the context of OR expression or OSN dynamics. Here, we determined when ORs exert thei...

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“…Remarkably, feedback inhibition does not require an OR promoter sequence. OR transgenes with synthetic promoters are also resistant to activation in mature OSNs, indicating that the OR coding sequence is sufficient for feedback inhibition to occur (Fleischmann et al 2013, Nguyen et al 2007). …”

Section: Chromatin-mediated Silencing Of Olfactory Receptor Genes Ismentioning

confidence: 99%

Monoallelic Expression of Olfactory Receptors

Monahan

Lomvardas

2015

Annu. Rev. Cell Dev. Biol.

151

148

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The sense of smell collects vital information about the environment by detecting a multitude of chemical odorants. Breadth and sensitivity are provided by a huge number of chemosensory receptor proteins, including more than 1,400 olfactory receptors (ORs). Organizing the sensory information generated by these receptors so that it can be processed and evaluated by the central nervous system is a major challenge. This challenge is overcome by monogenic and monoallelic expression of OR genes. The single OR expressed by each olfactory sensory neuron determines the neuron’s odor sensitivity and the axonal connections it will make to downstream neurons in the olfactory bulb. The expression of a single OR per neuron is accomplished by coupling a slow chromatin-mediated activation process to a fast negative-feedback signal that prevents activation of additional ORs. Singular OR activation is likely orchestrated by a network of interchromosomal enhancer interactions and large-scale changes in nuclear architecture.

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Functional Interrogation of an Odorant Receptor Locus Reveals Multiple Axes of Transcriptional Regulation

Abstract: A transgenic approach in mice allows the functional interrogation of an odorant receptor locus in vivo and reveals characteristics of its monogenic and monoallelic expression.

Cited by 24 publications

References 45 publications

Nuclear compartmentalization of odorant receptor genes

Nuclear compartmentalization of odorant receptor genes

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

Monoallelic Expression of Olfactory Receptors

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