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Constitutively expressed Protocadherin-α regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region.

Hasegawa S, Hirabayashi T, Kondo T, Inoue K, Esumi S, Okayama A, Hamada S, Yagi T - Front Mol Neurosci (2012)

Bottom Line: Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-α isoform and Pcdh-α's cytoplasmic region, but not OR specificity or neural activity.These results suggest that Pcdh-α proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity.The counterbalancing effect of Pcdh-α proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development.

View Article: PubMed Central - PubMed

Affiliation: KOKORO-Biology Group and CREST-JST, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University Osaka, Japan.

ABSTRACT
Olfactory sensory neuron (OSN) axons coalesce into specific glomeruli in the olfactory bulb (OB) according to their odorant receptor (OR) expression. Several guidance molecules enhance the coalescence of homotypic OSN projections, in an OR-specific- and neural-activity-dependent manner. However, the mechanism by which homotypic OSN axons are organized into glomeruli is unsolved. We previously reported that the clustered protocadherin-α (Pcdh-α) family of diverse cadherin-related molecules plays roles in the coalescence and elimination of homotypic OSN axons throughout development. Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-α isoform and Pcdh-α's cytoplasmic region, but not OR specificity or neural activity. These results suggest that Pcdh-α proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity. The counterbalancing effect of Pcdh-α proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development.

No MeSH data available.


Related in: MedlinePlus

Possible mechanism for the coalescence and elimination of homotypic OSN projections mediated by Pcdh-α proteins. In newborn mice, homotypic OSN axons coalesce by Type I attraction (green triangles). Type I attraction is performed by axon-target interaction by guidance molecules in a graded manner, e.g., Sama3A/Neuropilin1. Pcdh-α protein may elicit a contact-induced repulsion between homotypic OSN axons. In Pcdh-α-deficient mice, small glomeruli were generated because the contact-induced repulsive activity did not occur. During development, neural activity promotes Type II attraction (red triangles) and the Type II adhesion (red double-bars) of homotypic OSN projections. Type II attraction depends on axon-axon interactions during contact-induced repulsion between heterotypic OSN axons, e.g., mediated by EphA5/ephrin-A5. Type II adhesion results from the induction of expression of homophilic cell adhesion molecules, e.g., Kirrel2/Kirrel3. In small ectopic glomeruli, these attractive functions promote the correct coalescence of homotypic OSN projections and the elimination of ectopic projections. Pcdh-α protein may help to eliminate small ectopic glomeruli by the contact-induced repulsion of homotypic OSN axons. In adulthood, multiple small ectopic glomeruli disappear in WT mice, but are maintained in Pcdh-α-deficient mice. The interdependence of OSN coalescence could result from the balance between the neural-activity-induced attraction by guidance molecules and the contact-induced repulsion by Pcdh-α proteins in the glomerulus.
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Figure 10: Possible mechanism for the coalescence and elimination of homotypic OSN projections mediated by Pcdh-α proteins. In newborn mice, homotypic OSN axons coalesce by Type I attraction (green triangles). Type I attraction is performed by axon-target interaction by guidance molecules in a graded manner, e.g., Sama3A/Neuropilin1. Pcdh-α protein may elicit a contact-induced repulsion between homotypic OSN axons. In Pcdh-α-deficient mice, small glomeruli were generated because the contact-induced repulsive activity did not occur. During development, neural activity promotes Type II attraction (red triangles) and the Type II adhesion (red double-bars) of homotypic OSN projections. Type II attraction depends on axon-axon interactions during contact-induced repulsion between heterotypic OSN axons, e.g., mediated by EphA5/ephrin-A5. Type II adhesion results from the induction of expression of homophilic cell adhesion molecules, e.g., Kirrel2/Kirrel3. In small ectopic glomeruli, these attractive functions promote the correct coalescence of homotypic OSN projections and the elimination of ectopic projections. Pcdh-α protein may help to eliminate small ectopic glomeruli by the contact-induced repulsion of homotypic OSN axons. In adulthood, multiple small ectopic glomeruli disappear in WT mice, but are maintained in Pcdh-α-deficient mice. The interdependence of OSN coalescence could result from the balance between the neural-activity-induced attraction by guidance molecules and the contact-induced repulsion by Pcdh-α proteins in the glomerulus.

Mentions: Naris occlusion leads to sensory deprivation, which might inhibit the neural activity-regulated process by which multiple glomeruli are eliminated. Indeed, a previous study showed that this treatment significantly increases the number of glomeluli (Zou et al., 2004). Therefore, we next analyzed the number of M71 and MOR23 glomeruli between the closed and open sides of the OB to examine the effects of naris occlusion in the PcdhaΔCR/ΔCR or PcdhaΔCR2/ΔCR2 mice. Although the number of ectopic glomeruli was already significantly increased in these Pcdh-α-deficient mice, unilateral naris occlusion further increased the number of M71 and MOR23 glomeruli in the WT and Pcdh-α-deficient (PcdhaΔCR/ΔCR and PcdhaΔCR2/ΔCR2) mice until they all reached similar levels (Figure 9C). Thus, even in Pcdh-α-deficient mice, the ectopic glomeruli were further increased by reduced neural activity. Together, these findings further suggest that Pcdh-α proteins function continuously to organize the projections of OSN axons and eliminate ectopic glomeruli in a neural activity-independent manner (Figure 10).


Constitutively expressed Protocadherin-α regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region.

Hasegawa S, Hirabayashi T, Kondo T, Inoue K, Esumi S, Okayama A, Hamada S, Yagi T - Front Mol Neurosci (2012)

Possible mechanism for the coalescence and elimination of homotypic OSN projections mediated by Pcdh-α proteins. In newborn mice, homotypic OSN axons coalesce by Type I attraction (green triangles). Type I attraction is performed by axon-target interaction by guidance molecules in a graded manner, e.g., Sama3A/Neuropilin1. Pcdh-α protein may elicit a contact-induced repulsion between homotypic OSN axons. In Pcdh-α-deficient mice, small glomeruli were generated because the contact-induced repulsive activity did not occur. During development, neural activity promotes Type II attraction (red triangles) and the Type II adhesion (red double-bars) of homotypic OSN projections. Type II attraction depends on axon-axon interactions during contact-induced repulsion between heterotypic OSN axons, e.g., mediated by EphA5/ephrin-A5. Type II adhesion results from the induction of expression of homophilic cell adhesion molecules, e.g., Kirrel2/Kirrel3. In small ectopic glomeruli, these attractive functions promote the correct coalescence of homotypic OSN projections and the elimination of ectopic projections. Pcdh-α protein may help to eliminate small ectopic glomeruli by the contact-induced repulsion of homotypic OSN axons. In adulthood, multiple small ectopic glomeruli disappear in WT mice, but are maintained in Pcdh-α-deficient mice. The interdependence of OSN coalescence could result from the balance between the neural-activity-induced attraction by guidance molecules and the contact-induced repulsion by Pcdh-α proteins in the glomerulus.
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Related In: Results  -  Collection

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Figure 10: Possible mechanism for the coalescence and elimination of homotypic OSN projections mediated by Pcdh-α proteins. In newborn mice, homotypic OSN axons coalesce by Type I attraction (green triangles). Type I attraction is performed by axon-target interaction by guidance molecules in a graded manner, e.g., Sama3A/Neuropilin1. Pcdh-α protein may elicit a contact-induced repulsion between homotypic OSN axons. In Pcdh-α-deficient mice, small glomeruli were generated because the contact-induced repulsive activity did not occur. During development, neural activity promotes Type II attraction (red triangles) and the Type II adhesion (red double-bars) of homotypic OSN projections. Type II attraction depends on axon-axon interactions during contact-induced repulsion between heterotypic OSN axons, e.g., mediated by EphA5/ephrin-A5. Type II adhesion results from the induction of expression of homophilic cell adhesion molecules, e.g., Kirrel2/Kirrel3. In small ectopic glomeruli, these attractive functions promote the correct coalescence of homotypic OSN projections and the elimination of ectopic projections. Pcdh-α protein may help to eliminate small ectopic glomeruli by the contact-induced repulsion of homotypic OSN axons. In adulthood, multiple small ectopic glomeruli disappear in WT mice, but are maintained in Pcdh-α-deficient mice. The interdependence of OSN coalescence could result from the balance between the neural-activity-induced attraction by guidance molecules and the contact-induced repulsion by Pcdh-α proteins in the glomerulus.
Mentions: Naris occlusion leads to sensory deprivation, which might inhibit the neural activity-regulated process by which multiple glomeruli are eliminated. Indeed, a previous study showed that this treatment significantly increases the number of glomeluli (Zou et al., 2004). Therefore, we next analyzed the number of M71 and MOR23 glomeruli between the closed and open sides of the OB to examine the effects of naris occlusion in the PcdhaΔCR/ΔCR or PcdhaΔCR2/ΔCR2 mice. Although the number of ectopic glomeruli was already significantly increased in these Pcdh-α-deficient mice, unilateral naris occlusion further increased the number of M71 and MOR23 glomeruli in the WT and Pcdh-α-deficient (PcdhaΔCR/ΔCR and PcdhaΔCR2/ΔCR2) mice until they all reached similar levels (Figure 9C). Thus, even in Pcdh-α-deficient mice, the ectopic glomeruli were further increased by reduced neural activity. Together, these findings further suggest that Pcdh-α proteins function continuously to organize the projections of OSN axons and eliminate ectopic glomeruli in a neural activity-independent manner (Figure 10).

Bottom Line: Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-α isoform and Pcdh-α's cytoplasmic region, but not OR specificity or neural activity.These results suggest that Pcdh-α proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity.The counterbalancing effect of Pcdh-α proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development.

View Article: PubMed Central - PubMed

Affiliation: KOKORO-Biology Group and CREST-JST, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University Osaka, Japan.

ABSTRACT
Olfactory sensory neuron (OSN) axons coalesce into specific glomeruli in the olfactory bulb (OB) according to their odorant receptor (OR) expression. Several guidance molecules enhance the coalescence of homotypic OSN projections, in an OR-specific- and neural-activity-dependent manner. However, the mechanism by which homotypic OSN axons are organized into glomeruli is unsolved. We previously reported that the clustered protocadherin-α (Pcdh-α) family of diverse cadherin-related molecules plays roles in the coalescence and elimination of homotypic OSN axons throughout development. Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-α isoform and Pcdh-α's cytoplasmic region, but not OR specificity or neural activity. These results suggest that Pcdh-α proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity. The counterbalancing effect of Pcdh-α proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development.

No MeSH data available.


Related in: MedlinePlus