17–Beta–Estradiol Slows Photoreceptor Degeneration in Tubby (rd5/rd5) Mice During Early Postnatal Developmental Period

Abstract

Abstract: : Purpose: The tubby (rd5/rd5) mouse has been identified as an animal model for human Usher syndrome, the most common retinitis pigmentosa syndrome. Previously, we demonstrated that 17–beta–estradiol protects photoreceptor cells from light damage and hydrogen peroxide–induced retinal neuronal apoptosis (Yu et al., J Biol Chem 2004; Cao et al., Adv Exp Med Biol 2003). In this study, we tested the hypothesis that 17–beta–estradiol can slow photoreceptor degeneration in tubby mice. And the gene expression profile in response to 17–beta–estradiol in mouse retina was examined using microarray technique. Methods: The retinas from mice homozygous tub/tub, heterozygous tub/+ and wild–type C57BL/6J background +/+ were compared using quantitative histology. 17–beta–estradiol or progesterone or phenyl N–tert–Butyl Nitrone (PBN) was administered once a day by intraperitoneal injection starting at postnatal days 9 (P9). The total RNAs were isolated from the retinas of 17–beta–estradiol treated wild–type mice for microarray analysis. Real–Time quantitative reverse transcription–PCR (qRT–PCR) was performed to confirm the differentially expressed genes. Results:Measured by quantitative histology, between ages of P10 to P22, the thickness of outer nuclear layer (ONL) of tub/tub mice started thinning from P14, and a progressive photoreceptor loss thereafter. By P22, 40–50% of photoreceptors were lost. However, the systemic administration of 17–beta–estradiol significantly delayed photoreceptor loss during early postnatal developmental period while progesterone and PBN had no effects. Microarray data show that expressions of 570 (4%) genes were significantly affected by systematic administration of 17–beta–estradiol among 15,000 mouse genes tested. Eighty–nine genes that have ≥2–fold changes were grouped into 6 categories and selected for further analysis. Two apoptosis–associated genes, which were down–regulated, along with 12 other selected genes, were confirmed by qRT–PCR. Conclusions: The data demonstrated that 17–beta–estradiol can slow photoreceptor degeneration during the early postnatal developmental period in tubby mice, possibly through the slowing down of the apoptosis process as suggested by the microarray data. Further investigations are needed to elucidate the mechanisms underlying this protection.

Keywords: neuroprotection • retina • pathology: experimental