Limits...
Setting limits: maintaining order in a large gene family.

Abdus-Saboor I, Fleischmann A, Shykind B - Transcription (2014)

Bottom Line: Odorant receptor (OR) gene choice is a paradigmatic example of stochastic regulation in which olfactory neurons choose one OR from > 1,000 possibilities.Recent biochemical, mathematical, and in vivo findings have revealed key players, introduced new axes of control, and brought the core mechanisms of the process into sharper focus.

View Article: PubMed Central - PubMed

Affiliation: a Weill Cornell Medical College in Qatar; Qatar Foundation-Education City; Doha, Qatar.

ABSTRACT
Odorant receptor (OR) gene choice is a paradigmatic example of stochastic regulation in which olfactory neurons choose one OR from > 1,000 possibilities. Recent biochemical, mathematical, and in vivo findings have revealed key players, introduced new axes of control, and brought the core mechanisms of the process into sharper focus.

Show MeSH
Figure 1. Switching vs. Refinement. (A) Switching between two functional ORs was considered to represent the serial expression of OR alleles in which the neuron conducts a second random initiation of gene activation (circle of arrows) after the shutdown of the OR chosen by a prior selection. The neuron is initially OR1+ but then switches to become OR2+, maintaining the one-receptor-per-cell rule. (B) Refinement is proposed to maintain monogenic selection after a failure of the initiation process to generate the choice of a single OR allele. The neuron is temporarily double positive, OR1+OR2+, prior to a competitive process (opposing arrows) through which only one OR emerges.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4215173&req=5

Figure 1: Figure 1. Switching vs. Refinement. (A) Switching between two functional ORs was considered to represent the serial expression of OR alleles in which the neuron conducts a second random initiation of gene activation (circle of arrows) after the shutdown of the OR chosen by a prior selection. The neuron is initially OR1+ but then switches to become OR2+, maintaining the one-receptor-per-cell rule. (B) Refinement is proposed to maintain monogenic selection after a failure of the initiation process to generate the choice of a single OR allele. The neuron is temporarily double positive, OR1+OR2+, prior to a competitive process (opposing arrows) through which only one OR emerges.

Mentions: There is evidence for such a scenario. It can be argued that the puzzling observation of “wild type” switching represents just such an event. In wild type switching, lineage marking analyses revealed a history of two functional ORs having been active in the same OSN but with only one OR having persisted. This phenomenon was originally interpreted to have resulted from the serial expression of functional OR alleles, one shut off before the next was selected, through the same feedback process that prevented pseudogene expression (Fig. 1A and14). It is equally feasible that receptor expression could have occurred in parallel, with two ORs activated at once and the subsequent shutdown of one or the other. Further evidence may be seen when we attempted to force biallelic expression of the tet-P2 allele through the pervasive expression of the tTa. Despite the genetic potential for 100% coexpression of the the two tet-modified P2 alleles in each cell in the homozygous animal, biallelic expression was observed only 3% of the time, and in a predominantly younger subpopulation of OSNs.20 These findings suggest a developmental window exists after feedback and prior to full OSN maturation in which a refinement or failsafe mechanism may ensure singular OR choice. In this conception, wild type switching is not a consequence of the negative feedback program which, removes OR pseudogenes from the final expressed repertoire of the epithelium, but rather a result of a refinement process, possible resulting from an allelic competition, when more than one OR is expressed at the same time (Fig. 1B).


Setting limits: maintaining order in a large gene family.

Abdus-Saboor I, Fleischmann A, Shykind B - Transcription (2014)

Figure 1. Switching vs. Refinement. (A) Switching between two functional ORs was considered to represent the serial expression of OR alleles in which the neuron conducts a second random initiation of gene activation (circle of arrows) after the shutdown of the OR chosen by a prior selection. The neuron is initially OR1+ but then switches to become OR2+, maintaining the one-receptor-per-cell rule. (B) Refinement is proposed to maintain monogenic selection after a failure of the initiation process to generate the choice of a single OR allele. The neuron is temporarily double positive, OR1+OR2+, prior to a competitive process (opposing arrows) through which only one OR emerges.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215173&req=5

Figure 1: Figure 1. Switching vs. Refinement. (A) Switching between two functional ORs was considered to represent the serial expression of OR alleles in which the neuron conducts a second random initiation of gene activation (circle of arrows) after the shutdown of the OR chosen by a prior selection. The neuron is initially OR1+ but then switches to become OR2+, maintaining the one-receptor-per-cell rule. (B) Refinement is proposed to maintain monogenic selection after a failure of the initiation process to generate the choice of a single OR allele. The neuron is temporarily double positive, OR1+OR2+, prior to a competitive process (opposing arrows) through which only one OR emerges.
Mentions: There is evidence for such a scenario. It can be argued that the puzzling observation of “wild type” switching represents just such an event. In wild type switching, lineage marking analyses revealed a history of two functional ORs having been active in the same OSN but with only one OR having persisted. This phenomenon was originally interpreted to have resulted from the serial expression of functional OR alleles, one shut off before the next was selected, through the same feedback process that prevented pseudogene expression (Fig. 1A and14). It is equally feasible that receptor expression could have occurred in parallel, with two ORs activated at once and the subsequent shutdown of one or the other. Further evidence may be seen when we attempted to force biallelic expression of the tet-P2 allele through the pervasive expression of the tTa. Despite the genetic potential for 100% coexpression of the the two tet-modified P2 alleles in each cell in the homozygous animal, biallelic expression was observed only 3% of the time, and in a predominantly younger subpopulation of OSNs.20 These findings suggest a developmental window exists after feedback and prior to full OSN maturation in which a refinement or failsafe mechanism may ensure singular OR choice. In this conception, wild type switching is not a consequence of the negative feedback program which, removes OR pseudogenes from the final expressed repertoire of the epithelium, but rather a result of a refinement process, possible resulting from an allelic competition, when more than one OR is expressed at the same time (Fig. 1B).

Bottom Line: Odorant receptor (OR) gene choice is a paradigmatic example of stochastic regulation in which olfactory neurons choose one OR from > 1,000 possibilities.Recent biochemical, mathematical, and in vivo findings have revealed key players, introduced new axes of control, and brought the core mechanisms of the process into sharper focus.

View Article: PubMed Central - PubMed

Affiliation: a Weill Cornell Medical College in Qatar; Qatar Foundation-Education City; Doha, Qatar.

ABSTRACT
Odorant receptor (OR) gene choice is a paradigmatic example of stochastic regulation in which olfactory neurons choose one OR from > 1,000 possibilities. Recent biochemical, mathematical, and in vivo findings have revealed key players, introduced new axes of control, and brought the core mechanisms of the process into sharper focus.

Show MeSH