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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

M71 glomeruli in PcdhaΔA/ΔA and PcdhaΔCR/ΔCR mice. (A) X-gal-stained M71 glomeruli in WT (a–c) and PcdhaΔA/ΔA (d–f) mice at P30. Multiple small, extraneous glomeruli were seen. (B) M71 glomeruli in PcdhaΔCR/ΔCR (g–i) and PcdhaΔA/ΔA (j–l) mice at P7. The abnormalities found in PcdhaΔA/ΔA (ΔA/ΔA) mice were similar to those of PcdhaΔCR/ΔCR (ΔCR/ΔCR) mice through development (P7–P60). Unlike these mice, axonal coalescence of the PcdhaΔ(2–c2)/Δ(2–c2) mice appeared normal at least for the M71 and MOR23 OSNs (see Figure 7). Scale bars, 1 mm for panels (a) and (d), 500 μm for panels (b, c, e, f, g, and j), and 250 μm for panels (h, i, k, and l).
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Figure 8: M71 glomeruli in PcdhaΔA/ΔA and PcdhaΔCR/ΔCR mice. (A) X-gal-stained M71 glomeruli in WT (a–c) and PcdhaΔA/ΔA (d–f) mice at P30. Multiple small, extraneous glomeruli were seen. (B) M71 glomeruli in PcdhaΔCR/ΔCR (g–i) and PcdhaΔA/ΔA (j–l) mice at P7. The abnormalities found in PcdhaΔA/ΔA (ΔA/ΔA) mice were similar to those of PcdhaΔCR/ΔCR (ΔCR/ΔCR) mice through development (P7–P60). Unlike these mice, axonal coalescence of the PcdhaΔ(2–c2)/Δ(2–c2) mice appeared normal at least for the M71 and MOR23 OSNs (see Figure 7). Scale bars, 1 mm for panels (a) and (d), 500 μm for panels (b, c, e, f, g, and j), and 250 μm for panels (h, i, k, and l).

Mentions: PcdhaΔCR/ΔCR mice are presumptive mutants of the Pcdh-α locus; no Pcdh-α proteins are seen in the brain of these mice (Hasegawa et al., 2008). Another Pcdh-α mutant mouse, PcdhaΔA/ΔA, lacks the common cytoplasmic region (56 amino acids) of Pcdh-α A-type isoforms, and expresses a truncated Pcdh-α protein that lacks the A-type specific cytoplasmic tail (Katori et al., 2009). PcdhaΔA/ΔA mice show disrupted and diffuse serotonergic axon projections, similar to those of the PcdhaΔCR/ΔCR mice (Katori et al., 2009). To further address how the Pcdh-α proteins control the axonal coalescence of homotypic OSNs expressing specific ORs, we analyzed the axonal coalescence in PcdhaΔA/ΔA mice with the M71-IRES-taulacZ locus. We found a perturbed coalescence of M71 axons in the PcdhaΔA/ΔA mice at P30 (Figure 8A) and P7 (Figure 8B). Similar abnormalities were found in the PcdhaΔCR/ΔCR mice (Figure 8B, Hasegawa et al., 2008). Whole-mount analysis of the M71-IRES-taulacZ mice typically showed one labeled glomerulus per half-bulb at the lateral and medial side and in rare cases a second glomerulus; thus, there was an average of 1.1–1.2 glomeruli per lateral or medial side of the half-bulb at P30 in WT mice. In contrast, PcdhaΔA/ΔA mice showed a perturbed coalescence of M71 axons and significantly higher numbers of M71 glomeruli compared to WT mice (Table 2). These results indicated that the common cytoplasmic region among Pcdh-α proteins is required for both the initial coalescence of OSN axons and the elimination of glomeruli during development.


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)

M71 glomeruli in PcdhaΔA/ΔA and PcdhaΔCR/ΔCR mice. (A) X-gal-stained M71 glomeruli in WT (a–c) and PcdhaΔA/ΔA (d–f) mice at P30. Multiple small, extraneous glomeruli were seen. (B) M71 glomeruli in PcdhaΔCR/ΔCR (g–i) and PcdhaΔA/ΔA (j–l) mice at P7. The abnormalities found in PcdhaΔA/ΔA (ΔA/ΔA) mice were similar to those of PcdhaΔCR/ΔCR (ΔCR/ΔCR) mice through development (P7–P60). Unlike these mice, axonal coalescence of the PcdhaΔ(2–c2)/Δ(2–c2) mice appeared normal at least for the M71 and MOR23 OSNs (see Figure 7). Scale bars, 1 mm for panels (a) and (d), 500 μm for panels (b, c, e, f, g, and j), and 250 μm for panels (h, i, k, and l).
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Related In: Results  -  Collection

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Figure 8: M71 glomeruli in PcdhaΔA/ΔA and PcdhaΔCR/ΔCR mice. (A) X-gal-stained M71 glomeruli in WT (a–c) and PcdhaΔA/ΔA (d–f) mice at P30. Multiple small, extraneous glomeruli were seen. (B) M71 glomeruli in PcdhaΔCR/ΔCR (g–i) and PcdhaΔA/ΔA (j–l) mice at P7. The abnormalities found in PcdhaΔA/ΔA (ΔA/ΔA) mice were similar to those of PcdhaΔCR/ΔCR (ΔCR/ΔCR) mice through development (P7–P60). Unlike these mice, axonal coalescence of the PcdhaΔ(2–c2)/Δ(2–c2) mice appeared normal at least for the M71 and MOR23 OSNs (see Figure 7). Scale bars, 1 mm for panels (a) and (d), 500 μm for panels (b, c, e, f, g, and j), and 250 μm for panels (h, i, k, and l).
Mentions: PcdhaΔCR/ΔCR mice are presumptive mutants of the Pcdh-α locus; no Pcdh-α proteins are seen in the brain of these mice (Hasegawa et al., 2008). Another Pcdh-α mutant mouse, PcdhaΔA/ΔA, lacks the common cytoplasmic region (56 amino acids) of Pcdh-α A-type isoforms, and expresses a truncated Pcdh-α protein that lacks the A-type specific cytoplasmic tail (Katori et al., 2009). PcdhaΔA/ΔA mice show disrupted and diffuse serotonergic axon projections, similar to those of the PcdhaΔCR/ΔCR mice (Katori et al., 2009). To further address how the Pcdh-α proteins control the axonal coalescence of homotypic OSNs expressing specific ORs, we analyzed the axonal coalescence in PcdhaΔA/ΔA mice with the M71-IRES-taulacZ locus. We found a perturbed coalescence of M71 axons in the PcdhaΔA/ΔA mice at P30 (Figure 8A) and P7 (Figure 8B). Similar abnormalities were found in the PcdhaΔCR/ΔCR mice (Figure 8B, Hasegawa et al., 2008). Whole-mount analysis of the M71-IRES-taulacZ mice typically showed one labeled glomerulus per half-bulb at the lateral and medial side and in rare cases a second glomerulus; thus, there was an average of 1.1–1.2 glomeruli per lateral or medial side of the half-bulb at P30 in WT mice. In contrast, PcdhaΔA/ΔA mice showed a perturbed coalescence of M71 axons and significantly higher numbers of M71 glomeruli compared to WT mice (Table 2). These results indicated that the common cytoplasmic region among Pcdh-α proteins is required for both the initial coalescence of OSN axons and the elimination of glomeruli during development.

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