AUTHOR=Fazel Darbandi Siavash , Esau Crystal , Lesage-Pelletier Cindy , Monis Simon , Poitras Luc , Yu Man , Perin Sofia , Hatch Gary , Ekker Marc 

TITLE=Increased Sociability in Mice Lacking Intergenic Dlx Enhancers

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.718948

DOI=10.3389/fnins.2021.718948

ISSN=1662-453X

ABSTRACT=<p>The <italic>Dlx</italic> homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six <italic>Dlx</italic> genes organized into three convergently transcribed bigene clusters (<italic>Dlx1/2</italic>, <italic>Dlx3/4</italic>, and <italic>Dlx5/6</italic>) with <italic>cis</italic>-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the <italic>Dlx1/2</italic> and <italic>Dlx5/6</italic> 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 <italic>Dlx</italic> forebrain intergenic enhancers have been deleted (I56i<sup>(–/–)</sup>, I12b<sup>(–/–)</sup>). Loss of <italic>Dlx</italic> intergenic enhancers impairs expression of <italic>Dlx</italic> genes as well as some of their downstream targets or associated genes including <italic>Gad2</italic> and <italic>Evf2</italic>. The loss of the I56i enhancer resulted in a transient decrease in GABA<sup>+</sup> 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 <italic>Dlx</italic> intergenic enhancers will help us to further enhance our understanding of the role of these <italic>Dlx</italic> genes in forebrain development.</p>