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.

Neurotrophins play a crucial role in the development of the peripheral nervous system and their mRNAs are often regulated after several types of tissue injury. This study has investigated the regulation of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) mRNAs 30 min after myocardial ischaemia followed by reperfusion, by northern blotting, and in situ hybridization in a rat model. Between 2 and 120 h of reperfusion, Ngf mRNA levels showed two- to four-fold up-regulation compared with sham-operated hearts. Scattered Ngf-expressing cells, probably pericytes, were detected in the viable border zone of the myocardium in close association with capillaries, venules, and arterioles. In addition, diffuse Ngf expression was seen in the infarct area after 120 h of reperfusion. Bdnf mRNA showed transient up-regulation after 2 and 5 h of reperfusion and remained at control levels thereafter. Bdnf was expressed in the myocytes of the viable border zone. Nt-3 expression showed no significant changes compared with sham-operated hearts. These results suggest a role for NGF and/or BDNF in the pathogenesis of reperfusion injury or in the alterations of cardiac sensory and sympathetic neuronal function after myocardial ischaemia and reperfusion.

No abstract