Transcriptional regulation of Dlx expression in the subpallial telencephalon of vertebrates

Abstract

Vertebrate Dlx genes are required for the proper development of an array of tissues and organs including the forebrain, the branchial arches, the limbs and the sensory organs as well as bone and cartilage formation. Dlx genes code homeodomain proteins that act as transcription factors. Vertebrates have at least six Dlx genes that are organized into three convergently transcribed bigene clusters: Dlx1/Dlx2, Dlx5/Dlx6 and Dlx3/Dlx7. Dlx genes are often expressed with nested patterns along the proximo-distal axis of organs. Furthermore, Dlx paralogs show overlapping expression patterns and exhibit partially redundant functions. Yet, each paralog may also exhibit distinct function(s). Dlx1, Dlx2, Dlx5 and Dlx6 are expressed in a spatio-temporal manner in the basal ganglia of the developing telencephalon. These four genes are required for normal differentiation and migration of late-born progenitors in the subpallial telencephalon that will, subsequently, give rise to distinct subtypes of cortical GABAergic interneurons. I have identified two novel enhancers that regulate Dlx expression in the forebrain of vertebrates: URE2 (Upstream Regulatory Element 2) and I12b (Dlx1/Dlx2 intergenic enhancer 'b') located in the Dlx1/Dlx2 locus. Despite little sequence similarities, these enhancers shared overlapping activities in telencephalic domains with the previously described enhancers I5i1 and I56ii (Dlx5/Dlx6 intergenic enhancers 'i' and 'ii') from the Dlx5/Dlx6 locus. All four enhancers function where endogenous Dlx genes are expressed between E10.5 and birth. Yet, each enhancer targeted expression of a reporter gene to a different group(s) of cells in the basal ganglia and was characterized by a distinct profile of activity in tangentially migrating cells. These cells followed, between E12.5 and E15.5, migratory routes known to be Dlx-positive in vivo and gave rise to distinct subtypes of adult cortical interneurons. In addition, the differential activity of the Dlx enhancers identified several subdivisions in the medial and caudal ganglionic eminences (MGE and CGE) where distinct Dlx-progenitors are born. Consequently, the spatiotemporal regionalization of Dlx-progenitors and their acquisition of distinct molecular properties may explain the diversity of cortical interneuron subtypes derived from distinct ventral subdivisions.