Neurturin-Mediated Ret Activation Is Required for Retinal Function

Abstract

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␣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␣1 and GFR␣2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFR␣1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFR␣2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFR␣1, GFR␣2, or Ret was detected in photoreceptors or Müller 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.

Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation

“…2) which has been related to the supportive influence of microglia on neurons and macroglia (Harada et al 2002). Neurturin , a neutrophic factor required for normal retinal neuronal structure and function (Brantley et al 2008), was down-regulated with aging. Also, Egr1, a microglia-expressed transcription factor (Langmann et al 2009) implicated in neuroprotective immune mechanisms (Bakalash et al 2011; Sharma et al 2012), was found to decrease monotonically with age.…”

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

“…In mouse, ON starburst amacrine cells (SACs) expressing both PlexA2 and Sema6A form radially symmetric dendritic fields, which requires PlexA2/Sema6A repulsive action (Sun et al, 2013). Interestingly, Ret regulates the function and morphology of retinal ganglion cells (Brantley et al, 2008), which also express GDF-15 (Charalambous et al, 2013), indicating a possible common function in this system.…”

Multiple Endocrine Neoplasia

“…Coupling RET, its co-receptors, GNDF-family receptor alpha (GFRα 1–4) (198), and GNDF-family ligands leads to RET dimerization to form a heterohexamer complex that results in transcellular kinase activation and signaling. RET is involved in a number of cellular signaling pathways during development regulating the enteric nervous system progenitor cells, and neural crest and kidney progenitor cells (199–206). Basic studies suggest that RET is a component of the signaling pathway required for renal organogenesis and enteric neurogenesis (207,208).…”