Neurturin signalling via GFRalpha2 is essential for innervation of glandular but not muscle targets of sacral parasympathetic ganglion neurons.
Neurturin, a member of the glial cell-derived neurotrophic factor familys of ligands, is important for development of many cranial parasympathetic ganglion neurons. We have investigated the sacral component of the parasympathetic nervous system in mice with gene deletions for neurturin or its preferred receptor, GFRalpha2. Disruption of neurturin signalling decreased cholinergic VIP innervation to the mucosa of the reproductive organs, but not to the smooth muscle layers of these organs or to the urinary bladder. Thus, neurturin and its receptor are involved in parasympathetic innervation of a select group of pelvic visceral tissues. In contrast, noradrenergic innervation was not affected by the gene ablations. The epithelium of reproductive organs from knockout animals was atrophied, indicating that cholinergic innervation may be important for the maintenance of normal structure. Cholinergic neurons express GFRalpha2 on their terminals and somata, indicating they can respond to neurotrophic support, and their somata are smaller when neurturin signalling is disrupted. Colocalisation studies showed that many peripheral glia express GFRalpha2 although its role in these cells is yet to be determined. Our results indicate that neurturin, acting through GFRalpha2, is essential for parasympathetic innervation of the mucosae of reproductive organs, as well as for maintenance of a broader group of sacral parasympathetic neurons.
Wanigasekara
Y
Y
Prince of Wales Medical Research Institute and University of New South Wales, Randwick 2031, Australia.
Airaksinen
M S
MS
Heuckeroth
R O
RO
Milbrandt
J
J
Keast
J R
JR
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism; D005088:Exocrine Glands / Q000294:innervation*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005835:Genitalia / Q000294:innervation; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000294:innervation*; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism / Q000648:ultrastructure; D051101:Neurturin; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012447:Sacrum; D015398:Signal Transduction / Q000502:physiology; D001743:Urinary Bladder / Q000294:innervation; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism; D014781:Viscera / Q000294:innervation*
C494991:Gfra2 protein, mouse; C494992:Gfra2 protein, rat; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D051101:Neurturin; C495056:Nrtn protein, mouse; C495057:Nrtn protein, rat; D011518:Proto-Oncogene Proteins; D014660:Vasoactive Intestinal Peptide; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D000109:Acetylcholine