BMP4 regulates the hematopoietic stem cell niche.

Bone morphogenetic protein 4 (BMP4) is required for mesoderm commitment to the hematopoietic lineage during early embryogenesis. However, deletion of BMP4 is early embryonically lethal and its functional role in definitive hematopoiesis is unknown. Consequently, we used a BMP4 hypomorph to investigate the role of BMP4 in regulating hematopoietic stem cell (HSC) function and maintaining steady-state hematopoiesis in the adult. Reporter gene expression shows that Bmp4 is expressed in cells associated with the hematopoietic microenvironment including osteoblasts, endothelial cells, and megakaryocytes. Although resting hematopoiesis is normal in a BMP4-deficient background, the number of c-Kit+, Sca-1+, Lineage- cells is significantly reduced. Serial transplantation studies reveal that BMP4-deficient recipients have a microenvironmental defect that reduces the repopulating activity of wild-type HSCs. This defect is even more pronounced in a parabiosis model that demonstrates a profound reduction in wild-type hematopoietic cells within the bone marrow of BMP4-deficient recipients. Furthermore, wild-type HSCs that successfully engraft into the BMP4-deficient bone marrow show a marked decrease in functional stem cell activity when tested in a competitive repopulation assay. Taken together, these findings indicate BMP4 is a critical component of the hematopoietic microenvironment that regulates both HSC number and function.

Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis.

MUC1 is an integral membrane mucin glycoprotein that is normally expressed on the apical surface of most simple, secretory epithelia and hematopoietic cells. Overexpression of aberrantly glycosylated MUC1 is a hallmark of many carcinomas including 90% of breast carcinomas. MUC1 has been shown to bind to c-Src tyrosine kinase in vitro, whereby c-Src phosphorylates the MUC1 cytoplasmic domain at a YEKV motif. c-Src is an extensively studied nonreceptor tyrosine kinase implicated in mammary tumorigenesis. Previously, mouse mammary tumor virus-driven polyoma middle T-antigen (MMTV-PyV MT) transgenic mice crossed onto a Muc1 null background exhibited a significant delay in tumor progression. c-Src has been shown to interact with PyV MT, and to play an integral and indispensable role in MMTV-PyV MT-induced mammary tumorigenesis. Here, we determine the effect of Muc1 expression on c-Src activation and signaling. Examination of MMTV-PyV MT glands on a wild-type or Muc1 null background demonstrates that Muc1 expression promotes c-Src signaling by influencing its association with known substrates such as the p85 subunit of phosphatidylinositol 3-kinase and beta-catenin. These findings may provide a mechanism for the delay in tumor progression that is observed in the absence of Muc1.

The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum.

Mx proteins are induced by type I interferon and inhibit a broad range of viruses by undefined mechanisms. They are included within the dynamin family of large GTPases, which are involved in vesicle trafficking and share common biophysical features. These properties include the propensity to self-assemble, an affinity for lipids, and the ability to tubulate membranes. In this report we establish that human MxA, despite sharing only 30% homology with conventional dynamin, possesses many of these properties. We demonstrate for the first time that MxA self-assembles into rings that tubulate lipids in vitro, and associates with a specific membrane compartment in cells, the smooth endoplasmic reticulum.