Neurturin-mediated ret activation is required for retinal function

The glial cell line-derived neurotrophic factor ( GDNF) family ligands (GFLs) [GDNF, NRTN ( neurturin), ARTN (artemin), and PSPN (persephin)] interact with GDNF family receptors (GFR alpha s) and activate intracellular signaling through the Ret receptor tyrosine kinase. To characterize the role of Ret signaling in retinal activity, we examined Ret hypomorphic and Ret conditional mice using electroretinography. We found that aberrant Ret function resulted in markedly diminished scotopic and photopic responses. Using mice deficient in individual GFLs, we found that only NRTN deficiency led to reduced retinal activity. To determine the potential target cell type for NRTN, we examined the retinal expression of its coreceptors (GFR alpha 1 and GFR alpha 2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFR alpha 1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFR alpha 2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFR alpha 1, GFR alpha 2, or Ret was detected in photoreceptors or Muller cells, suggesting that these cells are not directly affected by Ret. Finally, detailed morphologic analyses of retinas from NRTN- and Ret-deficient mice demonstrated a reduction in normal horizontal cell dendrites and axons, abnormal extensions of horizontal cell and bipolar cell processes into the outer nuclear layer, and mislocalized synaptic complexes. These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice.