Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons (microarray)

The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors (TFs), regulatory elements (REs), and chromatin are thought to precisely regulate gene expression. In the medial ganglionic eminence (MGE), the NKX2-1 TF controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. We dissected the molecular functions of NKX2-1 by defining its chromosomal binding regions, regulation of gene expression and epigenetic state. NKX2-1 binding at distal REs led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, Nkx2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub- ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants. We examined RNA expression (microarray), genome-wide modified histone marks (ChIP-seq), and NKX2-1 and LHX6 binding (TF ChIP-seq) from medial ganglionic eminence (MGE) in WT and conditional Nkx2-1 null mutant mice.