Epithelia–Mesenchyme Interaction Plays an Essential Role in Transdifferentiation of Retinal Pigment Epithelium of silver Mutant Quail: Localization of FGF and Related Molecules and Aberrant Migration Pattern of Neural Crest Cells during Eye Rudiment Formation

Abstract

Homozygotes of the quail silver mutation, which have plumage color changes, also display a unique phenotype in the eye: during early embryonic development, the retinal pigment epithelium (RPE) spontaneously transdifferentiates into neural retinal tissue. Mitf is considered to be the responsible gene and to function similarly to the mouse microphthalmia mutation, and tissue interaction between RPE and surrounding mesenchymal tissue in organ culture has been shown to be essential for the initiation of the transdifferentiation process in which fibroblast growth factor (FGF) signaling is involved. The immunohistochemical results of the present study show that laminin and heparan sulfate proteoglycan, both acting as cofactors for FGF binding, are localized in the area of transdifferentiation of silver embryos much more abundantly than in wild-type embryos. More intense immunohistochemical staining with FGF-1 antibody, but not with FGF-2 antibody, is also found in the neural retina, RPE, and choroidal tissue of silver embryos than in wild-type embryos. HNK-1 immunohistochemistry revealed that clusters of HNK-1-positive cells (presumptive migrating neural crest cells) are frequently located around the developing eyes and in the posterior region of the silver embryonic eye. Finally, chick-quail chimerical eyes were made by grafting silver quail optic vesicles to chicken host embryos: in most cases, no transdifferentiation occurs in the silver RPE, but in a few cases, transdifferentiation occurs where silver quail cells predominate in the choroid tissue. These observations together with our previous in vitro study indicate that the silver mutation affects not only RPE cells but also cephalic neural crest cells, which migrate to the eye rudiment, and that these crest cells play an essential role in the transdifferentiation of RPE, possibly by modifying the FGF signaling pathway. The precise molecular mechanism involved in RPE-neural crest cell interaction is still unknown, and the quail silver mutation is considered to be a good experimental model for studying the role of neural crest cells in vertebrate eye development.

Isolation and characterization of heparan sulfate from various murine tissues

“…The role of HSPG in developmental stage of the embryonal eye [31] and GAG distribution in the different eye part of vertebrates [32] have been described, however, the disaccharide composition of adult vertebrate eye HS not been reported.…”

Activin signaling limits the competence for retinal regeneration from the pigmented epithelium

“…While the molecular basis for this loss in the competence of the RPE to regenerate retina in birds and mammals is not known, Araki et al (2002) reported that an interaction with the adjacent extra-ocular mesenchyme is critical for limiting RPE transdifferentiation. In addition, Fuhrmann et al (2000) reported that an activin-like factor released from the extra-ocular mesenchyme during development is necessary and sufficient for the induction of the RPE fate in the proximal part of the optic vesicle.…”

Retinal pigment epithelium development, plasticity, and tissue homeostasis

“…The avian mutant Silver quail exhibits transdifferentiation of RPE in a limited portion, which indicates that some specific tissue interactions between RPE and other neighboring tissues must take place in that area. When the RPE layer from Silver mutant embryos was isolated from surrounding tissues and placed into culture, transdifferentation was only observed when recombined with choroid (Araki et al, 2002; Araki et al, 1998). In frog, the choroid contains high concentrations of the basement membrane component laminin and in high levels of laminin, dissociated RPE cells migrate, loose their pigment, start to proliferate extensively and assume a neuroepithelial phenotype (Reh and Nagy, 1987).…”