**6. Role of retinoic acid in postnatal ocular growth**

To elucidate the role of atRA in the regulation of postnatal ocular growth, several studies have been carried out in which either atRA or non-specific atRA synthesis inhibitors (i.e., citral, disulfiram) were administered either systemically or locally in several animals undergoing visually induced changes in eye growth [12, 60, 61]. Results of studies using chicks and mammals to examine the role of atRA in emmetropization, myopia development and postnatal ocular growth are difficult to interpret due to species differences in the processes of scleral remodeling and in the mechanisms by which ocular length and refraction are modulated by visual stimuli [62]. Moreover, these studies are further complicated by the multiple targets of atRA within the eye and pleiotropic cellular responses to retinoid signaling [63]. The mammalian sclera consists of a single fibrous layer that undergoes scleral thinning, and increased distensibility during periods of ocular elongation and myopia development. Scleral thinning during myopia development in mammals is the consequence of decreased sulfated glycosaminoglycan and collagen synthesis [11, 64, 65]. In contrast, the chick sclera consists of both cartilaginous and fibrous scleral layers. Ocular elongation during induced myopia in chicks is the result of growth of the cartilaginous sclera, with increases in sulfated glycosaminoglycan synthesis, increased protein synthesis, and increased total scleral mass [27, 66–68]. In chicks, increased choroidal synthesis of atRA during recovery from form deprivation myopia results in inhibition of scleral proteoglycan synthesis and slowing of the rate of ocular elongation. In primates [11] and guinea pigs [12], choroidal atRA synthesis is increased in treated eyes following induced myopia, a condition that is also associated with decreased proteoglycan synthesis in the posterior sclera but, in contrast to chicks, results in increased ocular elongation and myopia due to weakening of the fibrous sclera and localized ectasia at the posterior ocular pole. Considering the negative effect of atRA on scleral proteoglycan synthesis in animals containing either a single fibrous sclera (i.e., guinea pigs, primates) as well as chicks that contain both cartilaginous and fibrous scleral layers [9, 11], choroidally derived atRA represents a mechanism to regulate ocular length and refraction common to multiple species.

 Furthermore, interpretation of experiments in which atRA agonists and atRA synthesis inhibitors are delivered either systemically or intraocularly is complicated by the widespread multicellular effects of atRA. Eye growth is increased following dietary delivery of atRA to chicks and is decreased after oral delivery of citral, a non-specific inhibitor of atRA synthesis [61]. Similarly, intraocular delivery of the non-specific atRA synthesis inhibitor, disulfiram, inhibited the development of form-deprivation myopia in chicks [60], a result generally opposite of what would be predicated if atRA acted to inhibit ocular elongation in chicks. It is likely that untargeted administration of atRA or use of non-specific atRA synthesis inhibitors that also inhibit other aldehyde dehydrogenases lead to multicellular effects that may differ from those mediated by endogenous atRA. We have recently developed a small molecule inhibitor, dichloro-all-*trans*-retinone (DAR) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2 [69]. It is hoped that DAR, or similar compounds can be used to modulate endogenous concentrations of atRA through specific inhibition of the RALDH isoenzymes within the eye for future experimental and clinical studies to elucidate the role of atRA on postnatal ocular growth and myopia development.
