Little is known of the molecular mechanisms whereby spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm 1,2 . Here we show that Zfp145, encoding the transcriptional repressor Plzf, has a crucial role in spermatogenesis. Zfp145 expression was restricted to gonocytes and undifferentiated spermatogonia and was absent in tubules of W/W v mutants that lack these cells. Mice lacking Zfp145 underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice before testis degeneration showed alterations in the expression profile of genes associated with spermatogenesis. These results identify Plzf as a spermatogoniaspecific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.

Invariant Natural Killer T cell (iNK Tcell) have an innate immunity-like rapidity of response and the capacity to modulate effector functions of other cells. We show that the BTB-ZF transcriptional regulator, PLZF, is specifically expressed in iNKT cells. iNKT cells develop in the absence of PLZF, but lack many innate T cell features. PLZF deficient iNKT cells accumulate in the lymph nodes rather than in the liver and do not have an activated phenotype or express NK markers. PLZF deficient iNKT cells do not secrete high levels of IL-4 and IFNγ upon activation, however some cells produce either IL-4 or IFNγ, but not both. PLZF, therefore, is an iNKT cell specific transcription factor that is necessary for full functionality.Nearly all hematopoietic cells mature in the bone marrow. In contrast, multipotent progenitor T cells leave the bone marrow and home to the thymus, where signals from stromal cells are required for commitment to the T lineage 1 . Once directed into the T lineage, the cells undergo a rigorous selection process that eliminates more than 95% of the candidate T cells. Full maturation requires the expression of a T cell receptor (TCR) that binds self-peptide:self-MHC complexes with sufficient avidity. At some point during development, T cells are directed into one of several distinct T cell lineages such as CD4 single positive "helper" cells, CD8 single positive "killer" cells or CD4 + CD25 + regulatory cells. Commitment to these various lineages defines the specialized functions of the cell, which is critical since each cell type plays an essential and distinct role for host defense. The genes responsible for directing multipotent T cell progenitors into the various lineages are largely unknown 2 .Correspondence and requests for materials should be addressed to D.B.S (Email: santangd@mskcc.org). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAmong the various lineages of T cells, invariant Natural Killer T cells (iNKT cells) have several unique phenotypic traits such as the expression of receptors typically associated with Natural Killer cells (NK cells), the constitutive expression of activation markers and extremely restricted TCR diversity 3 . iNKT cells express an identical TCRα chain and most use a TCRβ chain that utilizes the Vβ8.2 gene segment. This TCR confers specificity to the non-MHC encoded self-molecule, CD1d, which binds and presents glycolipids rather than the typical peptide cargo presented by conventional MHC molecules.iNKT cells are also functionally distinct. Of particular interest is their ability to secrete large quantities of a variety of cytokines only minutes after activation via the TCR 3 . The rapid response of these cells, the conserved nature of the TCR and their indirect ability to modulate the function of many different cell types of the immune system has led to the appreciation that iNKT cells lay at a functional cusp between the innate and adaptive immune systems 4 . The broad range of cytokines released by iNKT cells results in th...