The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity to respond to both T-dependent and T-independent type II antigens. However, these mice did have decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Moreover, purified WASP-deficient T cells showed markedly impaired proliferation and antigen receptor cap formation in response to anti-CD3epsilon stimulation. Yet, purified WASP-deficient B cells showed normal responses to anti-Ig stimulation. We discuss the implications of our findings regarding WASP function in receptor signaling and cytoskeletal reorganization in T and B cells and compare the effects of WASP deficiency in mice and humans.

The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liverspecific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2 À/À progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2 À/À liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2 À/À liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche. The remarkable regenerative capacity of the mammalian liver is well known (Fausto et al. 2006;Michalopoulos 2007). In response to liver cell loss, existing hepatocytes and cholangiocytes (bile duct cells) re-enter the cell cycle to maintain or restore the original liver volume and biliary tree. When pathological or experimental conditions that block hepatocyte proliferation also exist, facultative liver progenitor cells, known in rodents as ''oval cells'' (OCs) for their morphological appearance (Farber 1956), emerge and expand from the most terminal branches of the biliary tree (Fausto and Campbell 2003;Fausto 2004;Roskams et al. 2004;Alison 2005;Theise 2006). Like embryonic hepatoblasts (HBs), OCs are considered to be bipotential, and can give rise to both hepatocytes and cholangiocytes (Evarts et al. 1987;Sell 2001). Cells that are thought to be equivalent to OCs have been identified in humans, and are presumed to also be liver progenitors (Roskams et al. 2004). However, it has not been possible to define the origin, potential, or molecular features of human liver progenitor cells.Chemically induced liver tumors in mice often feature an initial expansion of OCs, suggesting that they can be the cell of origin of at least some liver tumors (Sell 2001;Roskams 2006). However, genetically defined animal models that feature primary OC expansion are rare (Jakubowski et al. 2005). Instead, OCs appear in some genetically engineered models of liver tumorigenesis, but only secondary to hepatocellular dysplasia/neoplasia and inflammation (Sandgren et al. 1989;Santoni-Rugiu et al. 1996;Lu...

Schwannomas are common sporadic nervous system tumors and diagnostic features of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves and cause severe neurological deficits and significant morbidity. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded the success of early rational therapies. An understanding of how heterogeneity develops in NF2-mutant schwannomas is critically needed to improve therapeutic options for these patients. We have found that loss of the membrane:actin cytoskeleton-associated NF2 tumor suppressor protein, merlin, yields unstable intrinsic polarity and enables Nf2-/- SCs to adopt distinct programs of coordinated autocrine ErbB ligand production, polarized signaling and metabolism according to nutrient availability. We validated biomarkers of these programs in a well-established mouse model of schwannoma. Our studies suggest a self-generating model of heterogeneity and identify biomarkers that can now be mapped to the variable clinical and therapeutic behaviors of human schwannomas.