Parasympathetic Innervation and Function of Endocrine Pancreas Requires the Glial Cell Line–Derived Factor Family Receptor α2 (GFRα2)
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Figures
- FIG. 1.
Localization of the GFRα2 protein in Schwann cells and parasympathetic nerve fibers in the wild-type mouse endocrine pancreas. A–C: Colocalization (C, yellow) of GFRα2 (A, red) and S100β (B, green) in islets of Langerhans. The GFRα2 protein is localized in S100β+ Schwann cells encircling the islets. Some S100β- and GFRα2-containing glial processes are also present in the center of the islets (small arrow). Arrowheads indicate thin and varicose GFRα2+ and S100β− nerve fiber distributed randomly in the center of the islet. D–I: Most GFRα2+ (D and G, red) thin varicose nerve fibers (arrowheads) express the parasympathetic markers VAChT (E, green) and VIP (H, green). Colocalization is seen in yellow (F and I). The arrow points indicate GFRα2+ varicosities that are VIP−. J–K: The parasympathetic markers, VAChT (J, red) and VIP (K, green), show similar varicose staining and are colocalized (L, yellow) in most nerve fibers in the islets (arrowheads). Note that some of the varicosities contain either VIP or VAChT but not both of the markers (arrows). M–O: GFRα2 (M, red) (arrowheads) is not expressed in sympathetic nerve fibers (arrows) labeled with TH (N, green) in the islets. Bar equals 50 μm.
- FIG. 2.
Reduced cholinergic innervation of islets of Langerhans in the GFRα2-KO mouse pancreas. A: VIP immunohistochemistry stains several varicose nerve fibers in wild-type islets. B: In the GFRα2-KO pancreas, many islet profiles are completely devoid of parasympathetic fibers (circled area in B), but some islets have apparently normal density of VIP+ innervation (arrow). D and E: Density of VAChT+ varicosities is reduced in GFRα2-KO islets. Bars equal 50 μm. C and F: Density histograms of islet parasympathetic innervation shown as percentage of islet profiles with a given density of immunopositive varicosities per islet area (arbitrary units). In the wild-type pancreas (▪), most islet profiles have moderate to high density of varicose, VIP+ (C), and VAChT+ (F) nerve fibers. In contrast, the number of islet profiles with low density of nerve fibers is greatly increased in the GFRα2-KO pancreas (□).
- FIG. 3.
Loss of vagally stimulated secretion of PP and insulin and diminished glucagon response in GFRα2-KO mice. A: In wild-type animals, 2-DG, a central vagal stimulant, induces secretion of PP. *P < 0.01 for WT vs. KO. After 30 min, plasma PP returned close to baseline levels in wild-type mice. In GFRα2-KO mice, 2-DG–induced PP secretion is absent. B: 2-DG induces secretion of insulin in wild-type but not GFRα2-KO mice. *P < 0.01 for WT baseline vs. 2-DG; †P < 0.001 for WT vs. KO. C: Secretion of glucagon is profoundly reduced in GFRα2-KO mice after 2-DG stimulation. *P < 0.001 for WT baseline vs. 2-DG; †P < 0.01 WT vs. KO; ‡P < 0.05 for KO baseline vs. 2-DG. D: Serum glucose levels before and after 2-DG. The glucose levels are measured from the same blood samples as in B. *P < 0.001 for WT baseline vs. 2-DG; †P < 0.001 for KO baseline vs. 2-DG. The number of animals in each group is presented in parentheses.
- FIG. 4.
Normal systemic glucose tolerance and insulin response in GFRα2-KO mice. Plasma glucose (A) and insulin (B) values are similar for wild-type and GFRα2-KO mice before and after an intraperitoneally administered glucose load (2 mg/g body wt).
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