We show that when telencephalic neural progenitors are briefly exposed to bone morphogenetic protein 2 (BMP2) in culture, their developmental fate is changed from neuronal cells to astrocytic cells. BMP2 significantly reduced the number of cells expressing microtubule-associated protein 2, a neuronal marker, and cells expressing nestin, a marker for undifferentiated neural precursors, but BMP2 increased the number of cells expressing S100-β, an astrocytic marker. In telencephalic neuroepithelial cells, BMP2 up-regulated the expression of negative helix–loop–helix (HLH) factors Id1, Id3, and Hes-5 (where Hes is homologue of hairy and Enhancer of Split) that inhibited the transcriptional activity of neurogenic HLH transcription factors Mash1 and neurogenin. Ectopic expression of either Id1 or Id3 (where Id is inhibitor of differentiation) inhibited neurogenesis of neuroepithelial cells, suggesting an important role for these HLH proteins in the BMP2-mediated changes in the neurogenic fate of these cells. Because gliogenesis in the brain and spinal cord, derived from implanted neural stem cells or induced by injury, is responsible for much of the failure of neuronal regeneration, this work may lead to a therapeutic strategy to minimize this problem.

Chromosomes and genes are nonrandomly arranged within the mammalian cell nucleus. However, the functional significance of nuclear positioning in gene expression is unclear. Here we directly probed the relationship between nuclear positioning and gene activity by comparing the location of the active and inactive copies of a monoallelically expressed gene in single cell nuclei. We demonstrate that the astrocyte-specific marker GFAP (glial fibrillary acidic protein) is monoallelically expressed in cortical astrocytes. Selection of the active allele occurs in a stochastic manner and is generally maintained through cell division. Taking advantage of the monoallelic expression of GFAP, we show that the functionally distinct alleles occupy differential radial positions within the cell nucleus and differentially associate with intranuclear compartments. In addition, coordinately regulated astrocyte-specific genes on distinct chromosomes spatially associate in their inactive state and dissociate upon activation. These results provide direct evidence for function-related differential positioning of individual gene alleles within the interphase nucleus.

The signaling systems of Notch and bone morphogenetic protein (BMP) are highly conserved from flies to mammals and have been shown to be important in the development of multiple organs. For instance, in the fate determination of mouse neuroepithelial cells, Notch signaling plays a role in keeping the progenitors from differentiating into neurons. BMP is also known to inhibit neuronal differentiation. In this paper, we show that BMP2 enhances Notch‐induced transcriptional activation of Hes‐5 and Hesr‐1 in mouse neuroepithelial cells. BMP2 stimulation, in addition to the introduction of the intracellular domain of Notch (NIC), resulted in enhanced activation of the Hes‐5 gene promoter. RBP‐Jκ binding to its target sequence is important not only for Notch signaling, but also for BMP2 signaling, to activate the Hes‐5 gene promoter. Smad1, a Smad species that is activated by BMP2, barely interacted with NIC, but did form a complex with NIC in the simultaneous presence of the coactivators P/CAF and p300. Recruitment of p300 to the NIC‐containing complex was facilitated by activated Smad1, which is suggested to contribute to BMP2‐mediated enhancement of Notch‐induced Hes‐5 expression. These data suggest a novel functional cooperation between Notch signaling and BMP signaling.