Abstract
BackgroundBoth bone morphogenetic proteins (BMPs) and histone deacetylases (HDACs) have previously been established to play a role in the development of the three major cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes. We have previously established a connection between these two protein families, showing that HDACs suppress BMP-promoted astrogliogenesis in the embryonic striatum. Since HDACs act in the nucleus to effect changes in transcription, an unbiased analysis of their transcriptional targets could shed light on their downstream effects on BMP-signaling.ResultsUsing neurospheres from the embryonic striatum as an in vitro system to analyze this phenomenon, we have performed microarray expression profiling on BMP2- and TSA-treated cultures, followed by validation of the findings with quantitative RT-PCR and protein analysis. In BMP-treated cultures we first observed an upregulation of genes involved in cell-cell communication and developmental processes such as members of BMP and canonical Wnt signaling pathways. In contrast, in TSA-treated cultures we first observed an upregulation of genes involved in chromatin modification and transcription. Interestingly, we could not record direct changes in the protein levels of canonical members of BMP2 signaling, but we did observe an upregulation of both the transcription factor STAT3 and its active isoform phospho-STAT3 at the protein level.ConclusionsSTAT3 and SMAD1/5/8 interact synergistically to promote astrogliogenesis, and thus we show for the first time that HDACs act to suppress BMP-promoted astrogliogenesis by suppression of the crucial partner STAT3.
Highlights
Both bone morphogenetic proteins (BMPs) and histone deacetylases (HDACs) have previously been established to play a role in the development of the three major cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes
We previously demonstrated that treatment of neuronal precursor cells derived from the ganglionic eminences (GE) with BMP2 or Trichostatin A (TSA) resulted in a reduction in the generation of neurons and oligodendrocytes and in an increase in the production of astrocytes [27]
The connection between BMP and Wnt signaling [36] as well as between HDACs and Wnt signaling [21] had been shown to be important for astroglial and oligodendroglial lineage commitment, and it will be of great interest to examine whether HDACs and BMPs share a common pathway in the regulation of oligodendrocyte differentiation, as we have shown for astrocyte differentiation in this work
Summary
Both bone morphogenetic proteins (BMPs) and histone deacetylases (HDACs) have previously been established to play a role in the development of the three major cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes. It is becoming increasingly evident that the regulation of genes involved in brain development occurs not just at the level of the expression of activating and inhibiting transcription factors, and at the epigenetic level, in the covalent modification of chromatin [11]. Core histones can be methylated, phosphorylated, ubiquitinated and acetylated, to name just the best-known chemical groups involved, and these small moieties regulate the chromatin structure and subsequent gene expression. Deacetylation is catalyzed by histone deacetylases (HDAC), a large group of enzymes which are classified, based upon their domain structure and sequence homology, into four gene families [13]. HDAC11 is the only histone deacetylase categorized to HDAC class IV [15]
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