The luxoid (lu) mutation in mice is shown to be essential for the self-renewal of adult germline stem cells. This mutation results in a nonsense mutation in the Plzf gene, which encodes a transcriptional repressor involved in maintaining the undifferentiated state of cells. Plzf is coexpressed with Oct4 in undifferentiated spermatogonia, indicating its role in stem cell maintenance. Luxoid mutant mice exhibit progressive loss of germ cells, with no successful colonization of recipient testes by their germ cells, suggesting that the defect is intrinsic to the stem cells. Transplantation experiments confirmed that germ cells from lu/lu males cannot colonize recipient testes, while wild-type germ cells can, indicating that the mutation is cell-autonomous. The Plzf protein, which is expressed in undifferentiated spermatogonia, is truncated in the luxoid mutant, lacking all nine zinc-finger domains. This mutation leads to the loss of germ cells and male infertility. The study supports the hypothesis that Plzf is required for the self-renewal of germline stem cells in mammals. The luxoid mutation was mapped to chromosome 9 and is associated with skeletal and infertility phenotypes. The findings highlight the critical role of Plzf in maintaining the undifferentiated state of germline stem cells and in the self-renewal process.The luxoid (lu) mutation in mice is shown to be essential for the self-renewal of adult germline stem cells. This mutation results in a nonsense mutation in the Plzf gene, which encodes a transcriptional repressor involved in maintaining the undifferentiated state of cells. Plzf is coexpressed with Oct4 in undifferentiated spermatogonia, indicating its role in stem cell maintenance. Luxoid mutant mice exhibit progressive loss of germ cells, with no successful colonization of recipient testes by their germ cells, suggesting that the defect is intrinsic to the stem cells. Transplantation experiments confirmed that germ cells from lu/lu males cannot colonize recipient testes, while wild-type germ cells can, indicating that the mutation is cell-autonomous. The Plzf protein, which is expressed in undifferentiated spermatogonia, is truncated in the luxoid mutant, lacking all nine zinc-finger domains. This mutation leads to the loss of germ cells and male infertility. The study supports the hypothesis that Plzf is required for the self-renewal of germline stem cells in mammals. The luxoid mutation was mapped to chromosome 9 and is associated with skeletal and infertility phenotypes. The findings highlight the critical role of Plzf in maintaining the undifferentiated state of germline stem cells and in the self-renewal process.