Abstract
The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters (Dlx1/2, Dlx3/4, and Dlx5/6) with cis-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and Dlx5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams–Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i(–/–), I12b(–/–)). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2. The loss of the I56i enhancer resulted in a transient decrease in GABA+ cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development.
Highlights
Dlx genes encode homeodomain transcriptional regulators that play multiple roles during embryonic development, notably in the forebrain, developing craniofacial skeleton and teeth, sensory organs and limbs
The Dlx bigene clusters are arranged in a convergent configuration with some of the enhancers located within the intergenic region
Mice that are homozygous for a single targeted deletion of I56i, I12b, or that have the variant I56i enhancer are viable, fertile, and do not show obvious developmental defects
Summary
Dlx genes encode homeodomain transcriptional regulators that play multiple roles during embryonic development, notably in the forebrain, developing craniofacial skeleton and teeth, sensory organs and limbs. Targeted mutations causing loss of function of individual Dlx genes often result in subtle phenotypes. When multiple Dlx genes are mutated such as in the case of the Dlx1(−/−) – Dlx2(−/−) double mutants, a more severe phenotype is observed that includes impaired migration and differentiation of GABAergic interneuron precursors (Anderson et al, 1997a,b). The six mouse Dlx genes are organized as three convergent bigene clusters Dlx1/Dlx, Dlx3/Dlx, and Dlx5/Dlx with relatively short intergenic regions (Stock et al, 1996; Ellies et al, 1997). The Dlx bigene clusters are arranged in a convergent configuration with some of the enhancers located within the intergenic region. The I56i and I56ii enhancers from the Dlx5/Dlx locus faithfully target expression
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