Tcf7l2/Tcf4 Transcriptional Repressor Function Requires HDAC Activity in the Developing Vertebrate CNS

Area of Science:

• Neuroscience
• Developmental Biology
• Epigenetics

Background:

• Neuronal subtype generation in the vertebrate CNS depends on precise progenitor gene regulation.
• Histone deacetylase (HDAC) proteins are implicated in cell specification, but their role in CNS neural progenitor fate is unclear.
• Tcf7l2/Tcf4 transcription factor is known to regulate ventral progenitor lineage segregation by repressing Nkx2.2 and Olig2.

Purpose of the Study:

• To investigate the role of HDAC activity in CNS neural progenitor fate specification.
• To determine if HDACs are required for Tcf7l2/Tcf4-mediated repression of Nkx2.2 and Olig2.
• To elucidate the co-factors involved in Tcf7l2/Tcf4-mediated repression.

Main Methods:

• Administration of HDAC inhibitors (VPA, TSA, sodium butyrate) in ovo to chick embryos.
• In vivo functional and pharmacological assays.
• Dominant-negative functional assays.

Main Results:

• HDAC inhibition disrupted normal progenitor gene segregation in the developing neural tube.
• HDAC activity is required for the differential repression of Nkx2.2 and Olig2 by Tcf7l2/Tcf4.
• Tcf7l2/Tcf4 repression requires Gro/TLE/Grg co-repressor factors.

Conclusions:

• HDAC activity is essential for CNS neural progenitor fate specification.
• The transcriptional repressor activity of Tcf7l2/Tcf4 involves functional interactions with HDAC and Gro/TLE/Grg co-factors.
• This interaction is crucial for the proper segregation of Nkx2.2 and Olig2 expressing cells from a common progenitor pool.