Retarded Growth and Deficits in the Enteric and Parasympathetic Nervous System in Mice Lacking GFRα2, a Functional Neurturin Receptor

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and a related protein, neurturin (NTN), require a GPI-linked coreceptor, either GFR alpha1 or GFR alpha2, for signaling via the transmembrane Ret tyrosine kinase. We show that mice lacking functional GFR alpha2 coreceptor (Gfra2-/-) are viable and fertile but have dry eyes and grow poorly after weaning, presumably due to malnutrition. While the sympathetic innervation appeared normal, the parasympathetic cholinergic innervation was almost absent in the lacrimal and salivary glands and severely reduced in the small bowel. Neurite outgrowth and trophic effects of NTN at low concentrations were lacking in Gfra2-/- trigeminal neurons in vitro, whereas responses to GDNF were similar between the genotypes. Thus, GFR alpha2 is a physiological NTN receptor, essential for the development of specific postganglionic parasympathetic neurons.

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…7 We found previously that IR impaired parasympathetic innervation similarly in adult mouse SMGs, whereas transient overexpression of Shh transgene in Keratin5 + epithelial cells rescued such damage in male mice by increasing production of neurotrophic factors such as brain-derived neurotrophic factor (Bdnf), nerve growth factor (Ngf), and Neurturin (Nrtn). 15 By examining the expression of glial cell line-derived neurotrophic factor family receptor a2 (GFRa2), a marker of parasympathetic nerve, 22 we confirmed that in SMGs 90 days after IR the impairment of GFRa2 expression by IR was significantly ameliorated by Ad-Shh instillation 3 or 30 days after IR in both male and female mice (n = 3, p < 0.05; Fig. 4A).…”

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

“…2B,D). These reductions are reminiscent of ENS deficits that appear in GDNF (decreased neuron number) or NRTN (decreased fiber density) deficient mice, indicating that Ret DN/+ mice have a combination of deficits resulting from an overall reduction in GFL-mediated Ret activation (Gianino et al, 2003;Heuckeroth et al, 1999;Rossi et al, 1999).…”

“…3A). While GDNFmediated Ret activation is crucial for formation of SPG neurons, NRTN and GFRα2 are necessary for SPG trophic maintenance and innervation of the intraorbital harderian glands (Heuckeroth et al, 1999;Rossi et al, 1999). The postnatal survival of Ret DN/+ mice allowed us to determine whether the SPG neurons that were generated are affected by the decreased Ret activity.…”

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spermatogenesis has been suggested following the analysis of mice that overexpress GDNF in the testes (Gianino et al, 2003;Heuckeroth et al, 1999;Meng et al, 2000;Rossi et al, 1999). Unfortunately, the perinatal lethality of Ret-null animals has made it impossible to study the postnatal roles of Ret, and to develop animal models that mimic Ret-related human diseases.

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Hirschsprung associated GDNF mutations do not prevent RET activation

“…However, it is difficult to attribute a role to the D150N and T154S changes in HSCR development since, although an interaction between GDNF and GFRa2 is detectable in vitro, this co-receptor is considered a specific partner of neurturin in vivo. 36 Finally, Chen et al 37 have demonstrated that deletions including the T154 and I211 residues abolished the GDNF ability to maintain motor neurons from the spinal cord. However, since such deletions also lack the complete a-helix and the finger domain fundamental to activate the GFRa1/RET receptor complex, their effect on GDNF activity is likely to be dependent on deprivation of whole structural regions rather than on the loss of single residues.…”