Molecular mechanism and evolutional significance of epithelial-mesenchymal interactions in the body- and tail-dependent metamorphic transformation of anuran larval skin.

The epidermis of an anuran larva is composed of apical and skein cells that are both mitotically active and self-renewed through larval life. In contrast, the epidermis of an adult frog, with typical stratified squamous epithelium composed of germinative basal, spinous, granular, and cornified cells, is histologically identical to the mammalian epidermis. Two important issues have not yet been addressed in the study of the development of anuran skin. One is the origin of adult basal cells in the larval epidermis and the other is the mechanism by which larval basal cells are transformed into adult basal cells in a region- (body- and tail-) dependent manner. The cell lineage relationship between the larval and adult epidermal cells was determined by examining the expression profiles of several genes that are expressed specifically in larval and/or adult epidermal cells and differentiation profiles of larval basal cells cultured in the presence of thyroid hormone (TH). Histological analyses using several markers led to the identification of the skin transformation center (STC) where the conversion of larval skin to the adult counterpart is taking place. The STC emerges at a specific place in the body skin and at a specific stage of larval development. The STC progressively "moves" into and "invades" the adjacent larval region of the trunk skin as a larva develops, converting the larval skin into the preadult skin, but never into the tail region. The larva to preadult skin conversion requires an epidermal-mesenchymal interaction. The genesis of preadult basal cells is suppressed in the tail epidermis due to the influence of underlying mesenchyme in the tail region. PDGF signaling is one of the molecular cues of epidermal-mesenchymal interactions. In addition, a unique feature of anuran skin metamorphosis is presented referring to the skin of other vertebrates. Histological comparisons of the skin among vertebrate species strongly suggested a similarity between the anuran larval skin and the teleost fish adult skin and between the anuran adult skin and the adult skin of other tetrapod species. Based on these similarities, the evolutional significance of anuran skin metamorphosis is proposed. Finally, studies are reviewed that reveal the molecular mechanism of anuran metamorphosis in relation to TH-TR-TRE signaling. The results of these studies suggest new aspects of the biological significance of TH, and also enable us to envision concerted regulations of the expression of a gene in the frame of the gene network responsible for metamorphic remodeling of larval tissues. The present review will contribute to an understanding of the molecular mechanism of region-dependent skin development of anurans from not only a metamorphic but also from an evolutional point of view, and will provide a new way to understand the biological significance of TH in anurans.