**3. Visual regulation of intraocular retinoic acid synthesis**

#### **3.1 Emmetropization: vision-dependent ocular growth regulation**

 Clinical and experimental evidence have indicated that postnatal eye growth is regulated, at least in part, by a vision-dependent "emmetropization" mechanism that acts to minimize refractive error through the coordinated regulation of the growth of the ocular tissues [21, 22]. Interruption of emmetropization in animal models, such as the chick, primate, and guinea pig, through the application of translucent occluders (form deprivation) causes a distortion in visual quality, which results in ocular growth and myopia through changes in the regulation of scleral extracellular matrix (ECM) remodeling [23–27]. Form deprivation-induced myopia is reversible; removal of the occluder and subsequent detection of myopic defocus results in a rapid cessation of axial growth and the eventual reestablishment of emmetropia (recovery) [24]. Even stronger evidence for the presence of an emmetropization mechanism comes from studies in which animals are fitted with either concave (minus) lenses or convex (plus) lenses that shifts the focal plane behind (hyperopic defocus) or in front of (myopic defocus) the retinal photoreceptors, respectively. In animals with functional emmetropization, the axial length of the lens-treated eye will increase or decrease until the retinal location has shifted to match that of the new focal plane [28–31]. The emmetropization mechanism does not require the central nervous system and appears to be regulated by locally produced chemical signals within the eye itself. When visual form deprivation is restricted to nasal or temporal visual

#### *Retinoic Acid in Ocular Growth Regulation DOI: http://dx.doi.org/10.5772/intechopen.84586*

 fields, excessive growth of the sclera is limited to that portion corresponding to the visually deprived part of the retina [32, 33]. Furthermore experimental myopia can be induced animals lacking a functional optic nerve [34–36], suggesting that the central nervous system is not required for the development of myopia. It is now generally accepted that visually guided eye growth is regulated by a series of locally generated chemical events that begin in the retina in response to specific visual stimuli and terminate in the sclera where they result in scleral extracellular matrix (ECM) remodeling, changes in ocular length and refractive status [37–42]. Therefore the elucidation of the chemical events responsible for visually-induced changes in ocular growth is of great interest as it may provide new avenues for the development of therapies to slow or prevent the progression of myopia.

### **3.2 Choroidal retinoic acid: a potential ocular growth regulator**

Several studies in a variety of animal models indicate that all-*trans*-retinoic acid (atRA) may be one of the chemical signals required for the regulation of eye growth during emmetropization [9, 11–13]. Mertz and Wallman [9] were the first to show that choroidal synthesis of atRA was increased in chick eyes during recovery from form deprivation myopia and following application of positive lenses (imposed myopic defocus), two visual conditions that cause a deceleration in ocular growth rates. Moreover, atRA was shown to be decreased in eyes undergoing form deprivation myopia and compensation for hyperopic defocus compared with the fellow control eye, conditions that stimulate ocular elongation. It was therefore suggested that choroidal atRA could act as a locally produced (within the eye) scleral growth modulator during visually guided ocular growth. atRA is an attractive candidate for a visually regulated ocular growth regulator because it is readily diffusible, has pronounced effects on scleral extracellular matrix metabolism, and exerts its effects through highly regulated, locally controlled synthesis and degradation.

Studies by Simon et al. [43] and Rada et al. [10] identified transcriptional changes in choroidal *RALDH2* in response to imposed defocus or recovery from in induced myopia. RALDH2 mRNA concentration was found to decrease in the choroid following treatment with negative lenses and to increase with positive lenses or during recovery from induced myopia. No changes were observed in the expression of the atRA metabolizing enzymes, *RALDH3*, *RDH10*, *CYP1B1*, *CYP26*, and transcript levels of choroidal *RALDH1* were undetectable [10]. Additionally, changes in choroidal RALDH2 protein concentrations and enzymatic activity in recovering eyes were reflective of the transcriptional changes in choroidal RALDH2 [14] suggesting that, in response to myopic defocus or recovery from induced myopia, the concentration of choroidal RALDH2 increases which, in turn, results in increased production of atRA. No RALDH activity was detected in the sclera or retina/RPE of control or treated chick eyes, indicating that the choroid is responsible for the majority of atRA synthesized in the chick eye [14].
