We generated double knock-out mice lacking the GM2/GD2 and the GD3 synthase gene by mating single gene mutants, and we analyzed the abnormal phenotypes of the mutant mice expressing only the GM3 ganglioside. We observed a refractory skin lesion that appeared primarily on the face of the mutant mice at 25 weeks after birth or later. Frequent scratching of the wound sites was observed in mutant mice with the skin injury, suggesting that it is a triggering factor that exacerbates the injury. This was confirmed by isolating mice in special cages for metabolic study in which the skin injury developed more rapidly. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites of the mutants, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching and the resulting skin lesion. The fact that sensory response to mechanical stimuli decreased while that to hot stimuli increased in the mutant mice supports this interpretation. Thus, only GM3-expressing mice displayed the important role of gangliosides in maintaining skin integrity via regulation of the peripheral nerves.