Fazel Darbandi Siavash, Esau Crystal, Lesage-Pelletier Cindy, Monis Simon, Poitras Luc, Yu Man, Perin Sofia, Hatch Gary, Ekker Marc
Department of Biology, University of Ottawa, Ottawa, ON, Canada.
Front Neurosci. 2021 Oct 4;15:718948. doi: 10.3389/fnins.2021.718948. eCollection 2021.
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.
同源结构域转录因子在GABA能中间神经元前体的分化和迁移中发挥重要作用。小鼠和人类基因组各有六个基因，这些基因被组织成三个反向转录的双基因簇（、和），其调控元件（CREs）位于每个簇的基因间区域。其中，分别来自和位点的I56i和I12b增强子在发育中的前脑中具有活性。I56i也是GTF2I的结合位点，GTF2I是一种转录因子，其功能与社交能力增强和威廉姆斯-贝伦综合征相关。在确定这些CREs对前脑发育的调控作用时，我们构建了突变小鼠品系，其中前脑基因间增强子已被删除（I56i、I12b）。基因间增强子的缺失会损害基因及其一些下游靶点或相关基因（包括和）的表达。I56i增强子的缺失导致发育中的前脑中GABA细胞短暂减少。基因间增强子突变体在恐惧条件反射试验中也表现出社交能力增强和学习缺陷。对具有突变基因间增强子的小鼠进行表征将有助于我们进一步加深对这些基因在前脑发育中作用的理解。
