tretinoin and Skin-Abnormalities

Abnormal dermatoglyphs on human volar skin have been reported in many syndromes, but little is known about the pathogenesis. Patterns of pads on rodent limb volar skin are homologous to human dermatoglyphs.. In previous studies, we showed that transplacental exposure to teratogens induced abnormal pads in mouse fetuses. Moreover, teratogens caused abnormal pad patterns at levels below those that caused skeletal malformations. In this study, we examined morphology and cytokinetics in developing abnormal pads. Pregnant mice were treated with all-trans-retinoic acid at 20 mg/kg orally at embryonal day (E) 12.5 (vaginal plug = E0). The hindlimbs of the embryos were harvested and observed under a light microscope and by scanning electron microscopy. Cell proliferation and cell death were estimated by 5-bromo-2'-deoxyuridine (BrdU) labeling, Nile blue A vital staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL).. Retinoic acid induced aplasia of the fibular tarsal pad and supernumerary interdigital pads on hindlimbs. Cell proliferation was observed in the area of developing pad, but cell death was very rarely seen in either normal or abnormal pads.. Retinoic acid disturbed pad patterning as a whole rather than individual pad formation.

Topics: Abnormalities, Drug-Induced; Animals; Bromodeoxyuridine; Cell Death; Cell Survival; Embryo, Mammalian; Female; Fibula; Foot Deformities, Congenital; Hindlimb; In Situ Nick-End Labeling; Mice; Microscopy, Electron, Scanning; Pregnancy; Skin; Skin Abnormalities; Tretinoin

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing.

Topics: Amphiregulin; Animals; Cattle; Cell Division; Dimerization; EGF Family of Proteins; Epidermal Cells; Epidermal Growth Factor; Epidermis; ErbB Receptors; Female; Gene Expression Regulation; Globins; Glycoproteins; Growth Substances; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Keratins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Rabbits; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Skin; Skin Abnormalities; Transcription, Genetic; Transcriptional Activation; Transforming Growth Factor alpha; Tretinoin

Topical all-trans retinoic acid (RA) has been shown to transform the horn-filled utriculi of the rhino mouse into normal follicles. We studied the early events by light and electron microscopy. Reduction in diameters of the utriculi was quantified by image analysis of whole mounts. Topical RA at 0.05% in ethanol/propylene glycol was applied daily and biopsies were taken after 1, 2, 3 and 6 days of treatment. By electron microscopy, after 3 days of RA treatment there was a great increase in the size and density of laminated membrane coating granules (MCGs) which had fused to the apical membranes of the upper granular cells. Thereafter, corneocytes within the lumina of the utriculi showed fewer desmosomes and a loss of intercellular material, accompanied by detachment from each other. Conversion to normal follicles was complete by 6 days. In whole mounts examined after 3 days of RA, there was a 75% reduction in the mean diameter of the utriculi. These results suggest that extrusion of the contents of enlarged MCGs into the intercellular corneocyte spaces facilitated separation of corneocytes, leading to rapid shedding, perhaps through the action of desmosome-lysing proteases. The conversion to normal follicles is consistent with the established role of retinoids in correcting abnormal differentiation.

Topics: Administration, Cutaneous; Animals; Cell Membrane; Epidermis; Epithelium; Extracellular Space; Male; Mice; Mice, Hairless; Mice, Mutant Strains; Microscopy, Electron; Skin; Skin Abnormalities; Tretinoin

Retinoic acid-induced transformation of reticulate scales to feather-like structures (Dhouailly and Hardy, '78) provides a useful model to study biochemical differentiation in avian skin. In this study, immunofluorescent analysis of reticulate scale-feathers (RSFs) indicates that they contain beta keratin in feather barbs and, thus, are true feathers, biochemically. Epidermal cells that would otherwise produce only alpha keratin in reticulate scales are induced to reorganize and differentiate into barb ridge cells that accumulate feather beta keratins. The mechanism for these dramatic morphological and biosynthetic responses to retinoic acid is unknown.

Topics: Animals; Chick Embryo; Feathers; Skin; Skin Abnormalities; Teratogens; Tretinoin