Stem-like cells in bone sarcomas: implications for tumorigenesis.

Bone sarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. Despite advances in medical and surgical management, survival rates for high-grade tumors have remained static at 50% to 70%. Tumor stem cells have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors.

ATF5 regulates the proliferation and differentiation of oligodendrocytes.

The transcription factor ATF5 is expressed in cells of the embryonic and neonatal ventricular zone/subventricular zone (VZ/SVZ), and must be down-regulated for their differentiation into neurons and astrocytes. Here, we show that ATF5 plays a major role in directing oligodendrocyte development. ATF5 is expressed by oligodendrocyte precursors but is absent from mature oligodendroglia.

Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes.

The mechanisms that regulate neural progenitor cell differentiation are primarily unknown. The transcription factor activating transcription factor 5 (ATF5) is expressed in neural progenitors of developing brain but is absent from mature astrocytes and neurons. Here, we demonstrate that ATF5 regulates the conversion of ventricular zone (VZ) and subventricular zone (SVZ) neural progenitors into astrocytes.

Lysophosphatidic acid induces clonal generation of mouse neurospheres via proliferation of Sca-1- and AC133-positive neural progenitors.

Neural stem/progenitor cells are clonogenic in vitro and produce neurospheres in serum-free medium containing epidermal growth factor (EGF) and fibroblast growth factor (FGF2). Here, we demonstrate that lysophosphatidic acid (LPA) instigated the clonal generation of neurospheres from dissociated mouse postnatal forebrain in the absence of EGF and FGF2. LPA induced proliferation of cells which co-expressed Sca-1 antigen and AC133, markers of primitive hematopoietic and neural stem/progenitor cells.

Neural stem and progenitor cells in nestin-GFP transgenic mice.

Neural stem cells generate a wide spectrum of cell types in developing and adult nervous systems. These cells are marked by expression of the intermediate filament nestin. We used the regulatory elements of the nestin gene to generate transgenic mice in which neural stem cells of the embryonic and adult brain are marked by the expression of green fluorescent protein (GFP).

Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons.

An important milestone in brain development is the transition of neuroprogenitor cells to postmitotic neurons. We report that the bZIP transcription factor ATF5 plays a major regulatory role in this process. In developing brain ATF5 expression is high within ventricular zones containing neural stem and progenitor cells and is undetectable in postmitotic neurons.

Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres.

Neural stem cells (NSCs) in vitro are able to generate clonal structures, "neurospheres," that exhibit intra-clonal neural cell-lineage diversity; i.e., they contain, in addition to NSCs, neuronal and glial progenitors in different states of differentiation.