Abstract
The generation of functionally distinct neuronal subtypes within the vertebrate central nervous system (CNS) requires the precise regulation of progenitor gene expression in specific neuronal territories during early embryogenesis. Accumulating evidence has implicated histone deacetylase (HDAC) proteins in cell specification, proliferation, and differentiation in diverse embryonic and adult tissues. However, although HDAC proteins have shown to be expressed in the developing vertebrate neural tube, their specific role in CNS neural progenitor fate specification remains unclear. Prior work from our lab showed that the Tcf7l2/Tcf4 transcription factor plays a key role in ventral progenitor lineage segregation by differential repression of two key specification factors, Nkx2.2 and Olig2. In this study, we found that administration of HDAC inhibitors (Valproic Acid (VPA), Trichostatin-A (TSA), or sodium butyrate) in chick embryos in ovo disrupted normal progenitor gene segregation in the developing neural tube, indicating that HDAC activity is required for this process. Further, using functional and pharmacological approaches in vivo, we found that HDAC activity is required for the differential repression of Nkx2.2 and Olig2 by Tcf7l2/Tcf4. Finally, using dominant-negative functional assays, we provide evidence that Tcf7l2/Tcf4 repression also requires Gro/TLE/Grg co-repressor factors. Together, our data support a model where the transcriptional repressor activity of Tcf7l2/Tcf4 involves functional interactions with both HDAC and Gro/TLE/Grg co-factors at specific target gene regulatory elements in the developing neural tube, and that this activity is required for the proper segregation of the Nkx2.2 (p3) and Olig2 (pMN) expressing cells from a common progenitor pool.
Highlights
Cell fate specification in the ventral neural tube of the vertebrate central nervous system (CNS) involves the translation of graded extracellular Sonic hedgehog (Shh) signaling into discrete progenitor territories that generate specific neuronal and glial subtypes [1,2,3]
Gro/TLE/Grg co-repressors have been shown to recruit Class I histone deacetylase proteins (HDACs) that function to silence gene expression through modification of DNA/chromatin compaction [6,8,14,15]
We first assayed whether HDAC activity was necessary for ventral progenitor patterning by examining Nkx2.2 and Olig2 expression after blocking endogenous HDAC activity in the spinal cord with Valproic Acid (VPA) [16], since prior studies have shown that numerous Class I HDACs are expressed in the developing chicken spinal cord [17]
Summary
Cell fate specification in the ventral neural tube of the vertebrate CNS involves the translation of graded extracellular Sonic hedgehog (Shh) signaling into discrete progenitor territories that generate specific neuronal and glial subtypes [1,2,3]. Gro/TLE family proteins have been widely studied for their role as transcriptional regulators [6] These proteins contain five identified domains that mediate tetramerization and binding to other proteins, and are thought to function as bridging factors that help assemble transcription-regulating repressor complexes at enhancers [6]. It has been shown that Gro/TLE/Grg recruit Class I histone deacetylase (HDAC) proteins in drosophila embryos and vertebrate cell lines, which may repress cognate transcription factor target genes by inducing chromatin compaction [9]. It remains unclear whether a similar mechanism accounts for Gro/TLE/Grg repression in other cell or tissue types
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