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Oxytocin Expression and Function in the Posterior Retina: A Novel Signaling Pathway

Significance Statement

 

Vision is critically dependent upon molecular interaction between retina photoreceptors (PR) and retinal pigment epithelial cells (RPE) that facilitate visual cycle, phagocytosis, and neuroprotection etc. This complex process demands the utilization of multiple signaling pathways as the developed visual system involves two distinct types of photoreceptors and a postmitotic tight layer of RPE cells. In the past, several candidates have been discovered to mediate PR-RPE communication such as ATP and glutamate. Given the complexity involved in the full proof signaling process, multiple signaling tracks will be required to meet the demand. Hence, the molecular origin of this signaling pathway is controversial. Historically, Oxytocin was described to be present in the retina but its location and function were not determined. Oxytocin is a neuropeptide containing nine amino acids. Traditionally, oxytocin is released by the pituitary gland to regulate childbirth and breast feeding the two important reproductive functions. Several studies have emerged, which establishes involvement of oxytocinergic signaling in organ development. We used both human and rhesus retina preparations to probe in the presence of both OXT and OXTR within the retina. The functional property of the OXTR was studied by live cell Ca2+ imaging in response to ligand activation of human RPE cells in culture. We reasoned that in order to qualify as a signaling molecule, OXT should be identified in the retina. OXT in the retina should activate OXTR of the retina and trigger an increase in intracellular Ca2+. In the paper by Halbach et. al., it was demonstrated that birth hormone oxytocin localizes to photoreceptors, especially cones and its receptor OXTR is found within the RPE cells. Furthermore, treating human RPE cells with OXT resulted into an increase in intracellular Ca2+ the so-called master signaling molecule by activation of OXTR.  In the absence of an elucidated molecular interaction in the outer retina, the findings in the paper describe a potential new candidate signaling molecule with significance to PR-RPE communication. Cone photoreceptors are responsible for day time fine vision, and we are dependent heavily on cone photoreceptors for our vision. The paper sets up the stage for a potential cone photoreceptor and RPE communication network, and it remains to be investigated how this contributes to our visual health and disease.

Figure Legend: OXT (green) and OXTR (red) in the Rhesus retina and increase in RPE cell Ca2+ upon OXT binding to its receptor. OXT- Oxytocin, OXTR- Oxytocin receptor, PR- Photoreceptor, and RPE- Retinal Pigment Epithelium.

Oxytocin Expression and Function in the Posterior Retina: A Novel Signaling Pathway

 

 

 

 

 

 

 

 

Journal Reference

Halbach P1, Pillers DA2, York N1, Asuma MP3, Chiu MA3, Luo W3, Tokarz S3, Bird IM4, Pattnaik BR5. Invest Ophthalmol Vis Sci. 2015 ;56(2):751-60.

Show Affiliations

1Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States The Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, Wisconsin, United States.

2Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, United States.

3Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States.

4Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States The Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, Wisconsin, United States Departments of Obstetrics/Gynecology, University of Wisconsin, Madison, Wisconsin, United States.

5Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.

 

Abstract

PURPOSE:

Oxytocin (OXT) is recognized as an ubiquitously acting nonapeptide hormone that is involved in processes ranging from parturition to neural development. Its effects are mediated by cell signaling that occurs as a result of oxytocin receptor (OXTR) activation. We sought to determine whether the OXT-OXTR signaling pathway is also expressed within the retina.

METHODS:

Immunohistochemistry using cell-specific markers was used to localize OXT within the rhesus retina. Reverse transcriptase PCR and immunohistochemistry were used to assess the expression of OXTR in both human and rhesus retina. Single-cell RT-PCR and Western blot analyses were used to determine the expression of OXTR in cultured human fetal RPE (hfRPE) cells. Human fetal RPE cells loaded with FURA-2 AM were studied by ratiometric Ca(2+) imaging to assess transient mobilization of intracellular Ca(2+) ([Ca(2+)]i).

RESULTS:

Oxytocin was expressed in the cone photoreceptor extracellular matrix of the rhesus retina. Oxytocin mRNA and protein were expressed in the human and rhesus RPE. Oxytocin mRNA and protein expression were observed in cultured hfRPE cells, and exposure of these cells to 100 nM OXT induced a transient 79 ± 1.5 nM increase of [Ca(2+)]i.

CONCLUSIONS:

Oxytocin and OXTR are present in the posterior retina, and OXT induces an increase in hfRPE [Ca(2+)]i. These results suggest that the OXT-OXTR signaling pathway is active in the retina. We propose that OXT activation of the OXTR occurs in the posterior retina and that this may serve as a paracrine signaling pathway that contributes to communication between the cone photoreceptor and the RPE.

Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

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