Summary
Postnatal oligodendrocyte progenitor cells (OPC) self-renew, generate mature oligodendrocytes, and are a cellular origin of oligodendrogliomas. We show that the proteoglycan NG2 segregates asymmetrically during mitosis to generate OPC cells of distinct fate. NG2 is required for asymmetric segregation of EGFR to the NG2+ progeny, which consequently activates EGFR and undergoes EGF-dependent proliferation and self-renewal. In contrast, the NG2− progeny differentiates. In a mouse model, decreased NG2 asymmetry coincides with premalignant, abnormal self-renewal rather than differentiation and with tumor-initiating potential. Asymmetric division of human NG2+ cells is prevalent in non-neoplastic tissue but is decreased in oligodendrogliomas. Regulators of asymmetric cell division are misexpressed in low-grade oligodendrogliomas. Our results identify loss of asymmetric division associated with the neoplastic transformation of OPC.
During the neoplastic progression, macrophages as well as dendritic and NK cells are attracted into the tumor site and initiate the immune response against transformed cells. They activate and present tumor antigens to T cells, which are then activated to kill tumor cells. However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression. It is notable that tumor-associated macrophages promote the proliferation of tumor cells directly by secreting growth factors. They also participate in tumor progression by acting on endothelial cells and thus promoting the neovascularization of the tumor. Tumor-associated macrophages are indeed key protagonists during angiogenesis and promote each step of the angiogenesis cascade.
The junctional adhesion molecules (JAMs) have been recently described as interendothelial junctional molecules and as integrin ligands. Here we show that JAM-B and JAM-C undergo heterophilic interaction in cell-cell contacts and that JAM-C is recruited and stabilized in junctional complexes by JAM-B. In addition, soluble JAM-B dissociates soluble JAM-C homodimers to form JAM-B/JAM-C heterodimers. This suggests that the affinity of JAM-C monomers to form dimers is higher for JAM-B than for JAM-C. Using antibodies against JAM-C, the formation of JAM-B/JAM-C heterodimers can be abolished. This liberates JAM-C from its vascular binding partner JAM-B and makes it available on the apical side of vessels for interaction with its leukocyte counterreceptor ␣ M  2 integrin. We demonstrate that the modulation of JAM-C localization in junctional complexes is a new regulatory mechanism for ␣ M  2 -dependent adhesion of leukocytes.
Significance
The pathogenesis of systemic lupus erythematosus, a complex autoimmune inflammatory disease triggered by genetic and environmental factors, is generally attributed to defects in lymphocyte function. We show that dendritic cells (DCs) also drive autoimmune disease in mice. Our observations that dysregulation of Toll-like receptor signaling (a key pathway that alerts the immune system of encounter with infectious agents) in DCs alone is sufficient to induce autoimmunity sheds new light on the pathogenesis of this disease. This work implies that DC-specific reduction of Toll-like receptor signaling may prove to be a highly specific approach to reduce the symptoms of autoimmune diseases.
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