BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis

Abstract

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-␤, 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. P recise mechanisms by which neurogenesis and gliogenesis are regulated in the central nervous system (CNS) remain to be elucidated. Fetal telencephalic neuroepithelial cells contain neural precursors that give rise to the neuronal lineage and the glial lineage, which includes astrocytes and oligodendrocytes (1, 2). The fate of neural precursors in the developing brain is believed to be determined by intrinsic cellular programs and by external cues, including the cytokines (1, 2). Bone morphogenetic protein 2 (BMP2) is a pleiotropic cytokine (3) that is active in many tissues including the CNS (for review, see ref. 4). The action of BMP2 is mediated by heterotetrameric serine͞ threonine kinase receptors and the downstream transcription factors Smad1, -5, or -8. After these transcription factors are phosphorylated on serines, they form a complex with a common mediator, Smad4, and the complex is translocated into the nucleus to activate transcription of specific genes (5-7). Inhibitory Smad proteins, Smad6 and Smad7, repress the action of BMP2 by inhibiting the receptor-mediated phosphorylation of Smad1, -5, or -8 or by competing with Smad4 for the binding to Smad1, -5, and -8 (5-10). BMP2 can promote telencephalic neuroepithelial cells to differentiate as astrocyte (11,12). We have further demonstrated (12, 13) that BMP2 and leukemia inhibitory factor (LIF) act synergistically to induce neuroepithelial cells to become astrocytes by forming a complex of the respective downstream transcription factors, Smads and STAT3, bridged by p300. In the present study, we demonstrate that BMP2 not only promotes astrocyte differentiation in cooperation with LIF but also alters the neurogenic cell fate of telencephalic progenitors so that they develop into astrocytic cells. We found tha...

Signaling by Bone Morphogenetic Proteins and Smad1 Modulates the Postnatal Differentiation of Cerebellar Cells

“…In cultures of sympathetic neurons, BMP treatment can induce dendritic outgrowth (Lein et al, 1995) and promote synaptotagmin I expression (Patzke et al, 2001), changes consistent with our findings. Brief treatment with BMPs can also induce cultures of neural precursor cells from embryonic mice (Nakashima et al, 2001) or oligodendrocytes from newborn rats (Grinspan et al, 2000) to differentiate into astrocytes. Many of these BMP-treated astrocytes have extensively branched processes, a morphology similar to that found in the cerebellar cultures.…”

Typical and atypical stem cells in the brain, vitamin C effect and neuropathology

“…For example, in high concentrations of Ngn1, BMP2 promotes neuronal diff erentiation. On the contrary, if Ngn1 levels fall, BMP2 promotes gliogenesis (Nakashima et al, 2001). Therefore, studying the different combinations that occur over time might provide insights into the patterns of cellular diff erentiation.…”

Self-renewal of teratocarcinoma and embryonic stem cells

“…BMP treatment suppresses neural determination and in combination with LIF is sufficient to sustain ES cell self-renewal without feeders or serum factors. BMP induces expression of members of the Id family of negative transcriptional modulators in various cell types (Nakashima et al, 2001;Ruzinova and Benezra, 2003). This induction of Ids also occurs in ES cells and is the critical contribution of BMP/GDF signalling to ES cell self-renewal, since constitutive expression of Id1, Id2 or Id3 circumvents the BMP/ GDF requirement.…”