JOURNAL OF NEUROCHEMISTRY | 2009 | 108 | 91–101 doi: 10.1111/j.1471-4159.2008.05739.x
*Department of Anatomy, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan Genetics and Development Division, Toronto Western Research Institute, University Health Network, Department of Ophthalmology and Visual Sciences and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada àUniversity of Ottawa Eye Institute and Ottawa Health Research Institute, Ottawa, Ontario, Canada
Abstract The retinas of staggerer mice, carrying a null mutation of Color vision is supported by retinal cone photoreceptors that, RORa, show significant down-regulation of Opn1sw, in most mammals, express two photopigments sensitive to Opn1mw, and Arr3. RORa acts in synergy with cone-rod short (S-opsin) or middle (M-opsin) wavelengths. Expression homeobox transcription factor (Crx), to activate the Opn1sw of the Opn1sw and Opn1mw genes, encoding S-opsin and promoter in vitro. Chromatin immunoprecipitation assays re- M-opsin, respectively, is under the control of nuclear veal that RORa directly binds to the Opn1sw promoter, receptors, including thyroid hormone receptor b2 (TRb2), Opn1mw locus control region, and the Arr3 promoter in vivo. retinoid X receptor c (RXRc), and RORb, a member of the Our data suggest that RORa plays a crucial role in cone retinoic acid receptor-related orphan receptor (ROR) family. development by directly regulating multiple cone genes. We now demonstrate that RORa, another member of the ROR Keywords: arrestin, cone photoreceptor, opsin, retina, family, regulates Opn1sw, Opn1mw, as well as Arr3 (cone RORa, staggerer. arrestin) in the mouse retina. RORa expression is detected in J. Neurochem. (2009) 108, 91–101. cones by postnatal day 3 and maintained through adulthood.
The vertebrate retina contains two types of photoreceptors: is expressed predominantly in dorsal cones (Sze´l et al. 1992; rods that function in dim light and cones that mediate color Applebury et al. 2000). vision in bright light. Most mammals have dichromatic color Several transcription factors have been identified that vision, supported by cones expressing two opsin photopig- regulate the spatial and temporal patterning of cone opsin ments sensitive to short (S-opsin) or middle (M-opsin) expression. Thyroid hormone receptor b2 (TRb2) and retinoid wavelengths (Ebrey and Koutalos 2001). Humans and other X receptor c (RXRc) act in concert to repress S-opsin primates have an additional cone photopigment sensitive to expression during the embryonic period and in the dorsal long wavelengths (L-opsin), and thus have trichromatic color region of the mature retina (Ng et al. 2001; Roberts et al. vision. Mutations affecting the cone opsin genes, as well as 2005). It has been suggested that the postnatal down-regulation other genes involved in cone phototransduction, are respon- of both TRb2 and RXRc promotes the onset of S-opsin sible for color vision defects of varying degrees of severity (Deeb 2004). Received July 22, 2008; revised manuscript received October 8, 2008; The expression of the cone opsin genes is under distinct accepted October 10, 2008. spatial and developmental controls. In mice, S-opsin expres- Address correspondence and reprint requests to H. Fujieda, Depart- sion starts at the late embryonic stage (Ng et al. 2001; ment of Anatomy, School of Medicine, Tokyo Women’s Medical Uni- Applebury et al. 2007), while M-opsin expression is induced versity, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. during the second postnatal week (Fei 2003). The majority of E-mail: [email protected] Abbreviations used: ChIP, chromatin immunoprecipitation; LCR, cones in the mature mouse retina co-express both S- and locus control region; PNA, peanut agglutinin; ROR, retinoic acid M-opsins (Applebury et al. 2000). However, S-opsin expres- receptor-related orphan receptor; RORE, ROR response element; RXR, sion is more concentrated in ventral cones, whereas M-opsin retinoid X receptor; TR, thyroid hormone receptor.