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Different requirements for GFRα2-signaling in three populations of cutaneous sensory neurons.

Kupari J, Airaksinen MS - PLoS ONE (2014)

Bottom Line: In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin.These results suggest that different factors drive target innervation in these three populations of neurons.In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.

ABSTRACT
Many primary sensory neurons in mouse dorsal root ganglia (DRG) express one or several GFRα's, the ligand-binding receptors of the GDNF family, and their common signaling receptor Ret. GFRα2, the principal receptor for neurturin, is expressed in most of the small nonpeptidergic DRG neurons, but also in some large DRG neurons that start to express Ret earlier. Previously, GFRα2 has been shown to be crucial for the soma size of small nonpeptidergic nociceptors and for their target innervation of glabrous epidermis. However, little is known about this receptor in other Ret-expressing DRG neuron populations. Here we have investigated two populations of Ret-positive low-threshold mechanoreceptors that innervate different types of hair follicles on mouse back skin: the small C-LTMRs and the large Aβ-LTMRs. Using GFRα2-KO mice and immunohistochemistry we found that, similar to the nonpeptidergic nociceptors, GFRα2 controls the cell size but not the survival of both C-LTMRs and Aβ-LTMRs. In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin. These results suggest that different factors drive target innervation in these three populations of neurons. In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

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MrgD+ DRG neurons in GFRα2-KO mice are smaller and deficient in epidermal innervation of hairy skin.(A–C) Extensive colocalization of EGFP and GFRα2 in MrgprdΔEGFPf mouse DRGs. (D) Virtually all MrgD+ neurons express GFRα2 (GFRα2+ cells/total MrgD+ cells, n = 4 animals). (E-G) MrgD+ DRG neurons are smaller in GFRα2-KO than in wild-type animals (G: WT 382±34 µm2, KO 202±15 µm2; the data are from 270 cells and three animals per genotype, chi-square -test). (H–L) MrgD+ epidermal innervation is denser in the hairy skin of wild-type than GFRα2-KO mice (L: back skin, WT 26.8±0.4, KO 14.5±2.0; dorsal paw, WT 14.2±1.0, KO 5.1±2.3 arbitrary units; the data are from two animals/genotype and 2–4 skin samples/animal). Scale bars: (A, E) 50 µm; (H) 20 µm.
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pone-0104764-g001: MrgD+ DRG neurons in GFRα2-KO mice are smaller and deficient in epidermal innervation of hairy skin.(A–C) Extensive colocalization of EGFP and GFRα2 in MrgprdΔEGFPf mouse DRGs. (D) Virtually all MrgD+ neurons express GFRα2 (GFRα2+ cells/total MrgD+ cells, n = 4 animals). (E-G) MrgD+ DRG neurons are smaller in GFRα2-KO than in wild-type animals (G: WT 382±34 µm2, KO 202±15 µm2; the data are from 270 cells and three animals per genotype, chi-square -test). (H–L) MrgD+ epidermal innervation is denser in the hairy skin of wild-type than GFRα2-KO mice (L: back skin, WT 26.8±0.4, KO 14.5±2.0; dorsal paw, WT 14.2±1.0, KO 5.1±2.3 arbitrary units; the data are from two animals/genotype and 2–4 skin samples/animal). Scale bars: (A, E) 50 µm; (H) 20 µm.

Mentions: GFRα2-signaling is crucial for proper IB4+ nonpeptidergic neuron size and innervation of the glabrous epidermis [7]. To investigate if this phenotype extends to hairy skin, we used mice in which the Mrgprd gene locus had been targeted with an EGFP expressing construct [9]. This gene encodes MrgD, a Mas-related G-protein coupled receptor specifically expressed in nonpeptidergic nociceptive neurons that represent a great majority (75%) of the IB4+ DRG neurons [9]. As expected, nearly all (>97%) EGFP-positive ( = MrgD+) neurons were positive for GFRα2 in wild-type (WT) DRGs (Fig. 1A–D). We also analyzed the size distribution of these cells and found that the MrgD+ neurons were drastically smaller in KO mice than in WT animals (Fig. 1E, F, G).


Different requirements for GFRα2-signaling in three populations of cutaneous sensory neurons.

Kupari J, Airaksinen MS - PLoS ONE (2014)

MrgD+ DRG neurons in GFRα2-KO mice are smaller and deficient in epidermal innervation of hairy skin.(A–C) Extensive colocalization of EGFP and GFRα2 in MrgprdΔEGFPf mouse DRGs. (D) Virtually all MrgD+ neurons express GFRα2 (GFRα2+ cells/total MrgD+ cells, n = 4 animals). (E-G) MrgD+ DRG neurons are smaller in GFRα2-KO than in wild-type animals (G: WT 382±34 µm2, KO 202±15 µm2; the data are from 270 cells and three animals per genotype, chi-square -test). (H–L) MrgD+ epidermal innervation is denser in the hairy skin of wild-type than GFRα2-KO mice (L: back skin, WT 26.8±0.4, KO 14.5±2.0; dorsal paw, WT 14.2±1.0, KO 5.1±2.3 arbitrary units; the data are from two animals/genotype and 2–4 skin samples/animal). Scale bars: (A, E) 50 µm; (H) 20 µm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128720&req=5

pone-0104764-g001: MrgD+ DRG neurons in GFRα2-KO mice are smaller and deficient in epidermal innervation of hairy skin.(A–C) Extensive colocalization of EGFP and GFRα2 in MrgprdΔEGFPf mouse DRGs. (D) Virtually all MrgD+ neurons express GFRα2 (GFRα2+ cells/total MrgD+ cells, n = 4 animals). (E-G) MrgD+ DRG neurons are smaller in GFRα2-KO than in wild-type animals (G: WT 382±34 µm2, KO 202±15 µm2; the data are from 270 cells and three animals per genotype, chi-square -test). (H–L) MrgD+ epidermal innervation is denser in the hairy skin of wild-type than GFRα2-KO mice (L: back skin, WT 26.8±0.4, KO 14.5±2.0; dorsal paw, WT 14.2±1.0, KO 5.1±2.3 arbitrary units; the data are from two animals/genotype and 2–4 skin samples/animal). Scale bars: (A, E) 50 µm; (H) 20 µm.
Mentions: GFRα2-signaling is crucial for proper IB4+ nonpeptidergic neuron size and innervation of the glabrous epidermis [7]. To investigate if this phenotype extends to hairy skin, we used mice in which the Mrgprd gene locus had been targeted with an EGFP expressing construct [9]. This gene encodes MrgD, a Mas-related G-protein coupled receptor specifically expressed in nonpeptidergic nociceptive neurons that represent a great majority (75%) of the IB4+ DRG neurons [9]. As expected, nearly all (>97%) EGFP-positive ( = MrgD+) neurons were positive for GFRα2 in wild-type (WT) DRGs (Fig. 1A–D). We also analyzed the size distribution of these cells and found that the MrgD+ neurons were drastically smaller in KO mice than in WT animals (Fig. 1E, F, G).

Bottom Line: In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin.These results suggest that different factors drive target innervation in these three populations of neurons.In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.

ABSTRACT
Many primary sensory neurons in mouse dorsal root ganglia (DRG) express one or several GFRα's, the ligand-binding receptors of the GDNF family, and their common signaling receptor Ret. GFRα2, the principal receptor for neurturin, is expressed in most of the small nonpeptidergic DRG neurons, but also in some large DRG neurons that start to express Ret earlier. Previously, GFRα2 has been shown to be crucial for the soma size of small nonpeptidergic nociceptors and for their target innervation of glabrous epidermis. However, little is known about this receptor in other Ret-expressing DRG neuron populations. Here we have investigated two populations of Ret-positive low-threshold mechanoreceptors that innervate different types of hair follicles on mouse back skin: the small C-LTMRs and the large Aβ-LTMRs. Using GFRα2-KO mice and immunohistochemistry we found that, similar to the nonpeptidergic nociceptors, GFRα2 controls the cell size but not the survival of both C-LTMRs and Aβ-LTMRs. In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin. These results suggest that different factors drive target innervation in these three populations of neurons. In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

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