1. An Inducible Lentiviral Guide RNA Platform Enables the Identification of Tumor-Essential Genes and Tumor-Promoting Mutations In Vivo

    Cell Reports 10(8):1422 (2015) PMID 25732831

    The CRISPR/Cas9 technology enables the introduction of genomic alterations into almost any organism; however, systems for efficient and inducible gene modification have been lacking, especially for deletion of essential genes. Here, we describe a drug-inducible small guide RNA (sgRNA) ...
  2. Bcl-2 Antagonists Kill Plasmacytoid Dendritic Cells From Lupus-Prone Mice and Dampen Interferon-α Production.

    Arthritis & rheumatology (Hoboken, N.J.) 67(3):797 (2015) PMID 25418983

    Interferon-α (IFNα)-producing plasmacytoid dendritic cells (PDCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). IFNα-related genes are highlighted among SLE susceptibility alleles and are characteristically expressed in the blood of patients with SLE, while in mouse m...
  3. Maintaining dendritic cell viability in culture.

    Molecular Immunology 63(2):264 (2015) PMID 25081090

    When mouse dendritic cells (DCs) are isolated from tissues, purified and placed in a nutritive culture they die more rapidly than would be expected from their normal turnover in vivo. This can distort culture assays of DC function. We therefore tested several approaches to prolonging DC survival...
  4. Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes.

    Diabetologia 58(1):140 (2015) PMID 25301392

    Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the develop...
  5. Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes.

    Diabetologia 58(1):140 (2015) PMID 25301392

    Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the develop...
  6. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice.

    Blood 124(26):3939 (2014) PMID 25368374

    Apoptosis plays a role in normal lymphopoiesis and lymphoid malignancies. Pro-survival MCL-1 is essential for survival of T-cell progenitors, BCL-XL for immature thymocytes, and BCL-2 for mature T cells. Conversely, little is known about the regulators that are required for the survival of T-cel...
  7. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice.

    Blood 124(26):3939 (2014) PMID 25368374

    Apoptosis plays a role in normal lymphopoiesis and lymphoid malignancies. Pro-survival MCL-1 is essential for survival of T-cell progenitors, BCL-XL for immature thymocytes, and BCL-2 for mature T cells. Conversely, little is known about the regulators that are required for the survival of T-cel...
  8. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice.

    Blood 124(26):3939 (2014) PMID 25368374

    Apoptosis plays a role in normal lymphopoiesis and lymphoid malignancies. Pro-survival MCL-1 is essential for survival of T-cell progenitors, BCL-XL for immature thymocytes, and BCL-2 for mature T cells. Conversely, little is known about the regulators that are required for the survival of T-cel...
  9. The physiological relevance of death receptor-mediated apoptosis.

    Nature Reviews: Molecular Cell Biology 15(10):633 (2014) PMID 25207441

  10. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming.

    EMBO Reports 15(9):982 (2014) PMID 24990442 PMCID PMC4198042

    A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essenti...
  11. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming.

    EMBO Reports 15(9):982 (2014) PMID 24990442

    A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essenti...
  12. Plasmacytomagenesis in Eμ-v-abl transgenic mice is accelerated when apoptosis is restrained.

    Blood 124(7):1099 (2014) PMID 24986687 PMCID PMC4133484

    Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We previously showed that mice expressing an Eµ-v-abl oncogene solely develop plasmacytomas. Here we show that loss of the proapoptotic BH3-only protein Bim or, to a lesser extent, overexpression of antiapo...
  13. PUMA regulates germ cell loss and primordial follicle endowment in mice.

    Reproduction 148(2):211 (2014) PMID 24859845

    The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulato...
  14. PUMA regulates germ cell loss and primordial follicle endowment in mice.

    Reproduction 148(2):211 (2014) PMID 24859845

    The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulato...
  15. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.

    Cell Reports 7(6):1796 (2014) PMID 24882010

    X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show that loss of ...
  16. XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation

    Cell Reports 7(6):1796 (2014)

    X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show tha...
  17. Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf.

    Blood 123(17):2652 (2014) PMID 24632712 PMCID PMC3999752

    BH3 domain-only proteins (BH3-only) proteins are members of the Bcl-2 family that play crucial roles in embryogenesis and the maintenance of tissue homeostasis by triggering apoptotic cell death. The BH3-only protein Bim is critical for developmental apoptosis of lymphocytes, securing establishm...
  18. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner.

    Blood 123(16):2562 (2014) PMID 24497535

    Loss of inhibitor of apoptosis proteins (IAPs), particularly cIAP1, can promote production of tumor necrosis factor (TNF) and sensitize cancer cell lines to TNF-induced necroptosis by promoting formation of a death-inducing signaling complex containing receptor-interacting serine/threonine-prote...
  19. Loss of the proapoptotic BH3-only protein BCL-2 modifying factor prolongs the fertile life span in female mice.

    Biology of Reproduction 90(4):77 (2014) PMID 24571986

    The duration of the female fertile life span is influenced by the number of oocytes stored in the ovary as primordial follicles. Cell death, both during ovarian development in the embryo and in the postnatal ovary, plays a critical role in determining how many primordial follicles are establishe...
  20. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.

    Nature Medicine 20(3):283 (2014) PMID 24487434

    Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development o...