Morphological abnormalities in the ureter of type XVII collagen-deficient mice.

Non-fibrillar type XVII collagen (COL17A1) is a hemidesmosomal component of the epidermis and a key skin-disease molecule. We previously reported that COL17A1 is expressed in the urothelium of multiple species at low constitutive or in inducible levels. To clarify its function in the ureter, Col17a1-knockout (KO) mice were examined from 2 to 12 weeks of age. After 4 weeks, Col17a1-KO mice showed shorter ureteral length, smaller cross-sectional area, and disorganized urothelial layers compared with wild-type littermates, accompanied by systemic growth retardation. At 4 and/or 12 weeks, Col17a1-KO urothelium exhibited a higher epithelial area ratio, loss of polarity, intraluminal cells, lumen narrowing, and indistinct mucosal folds. Abnormalities were evident as early as 2 weeks, particularly in umbrella cells, which showed altered apical surfaces, hypertrophy, smaller vesicles, and shortened interdigitations. RNA-seq of 2-week-old Col17a1-KO ureters revealed upregulation of immune-related genes and downregulation of epithelial development genes. Uroplakin 2, a key urothelial molecule, was reduced in Col17a1-KO ureters at 1 day and 2 weeks but not at 12 weeks. Its transcription factor, forkhead box protein A1, was persistently reduced, with markedly lower protein expression in umbrella cells. These findings indicate that urothelial COL17A1 is essential for proper urothelial differentiation during postnatal development.