Increased Sociability in Mice Lacking Intergenic Enhancers

The homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six genes organized into three convergently transcribed bigene clusters (, , and ) with -regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the and 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 forebrain intergenic enhancers have been deleted (I56i, I12b). Loss of intergenic enhancers impairs expression of genes as well as some of their downstream targets or associated genes including and . 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 intergenic enhancers will help us to further enhance our understanding of the role of these genes in forebrain development.