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The Journal of Neuroscience, April 16, 2008, 28(16):4123-4135; doi:10.1523/JNEUROSCI.0249-08.2008

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Development/Plasticity/Repair
Neurturin-Mediated Ret Activation Is Required for Retinal Function

Milam A. Brantley, Jr,¹ Sanjay Jain,^2,3 Emily E. Barr,¹ Eugene M. Johnson, Jr,^3,4,5 and Jeffrey Milbrandt^3,5,6

¹Department of Ophthalmology and Visual Sciences, ²Department of Medicine, Renal Division, ³Hope Center for Neurological Disorders, and Departments of ⁴Molecular Biology and Pharmacology, ⁵Neurology, and ⁶Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to either of the following: Dr. Milam A. Brantley Jr, Department of Ophthalmology and Visual Sciences, Campus Box 8096, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: brantley{at}vision.wustl.edu; or Dr. Jeffrey Milbrandt, Department of Pathology, Campus Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: jmilbrandt{at}wustl.edu

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) [GDNF, NRTN (neurturin), ARTN (artemin), and PSPN (persephin)] interact with GDNF family receptors (GFRs) 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 (GFR1 and GFR2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFR1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFR2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFR1, GFR2, 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.

Key words: RET; neurturin; retina; ERG; horizontal; outer plexiform layer

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Received Jan. 18, 2008; revised Feb. 24, 2008; accepted March 4, 2008.

Correspondence should be addressed to either of the following: Dr. Milam A. Brantley Jr, Department of Ophthalmology and Visual Sciences, Campus Box 8096, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: brantley{at}vision.wustl.edu; or Dr. Jeffrey Milbrandt, Department of Pathology, Campus Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: jmilbrandt{at}wustl.edu

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