2. striatopallidal neurons. These two neuronal populations play unique roles in controlling movement-related functions in the basal ganglia circuits. An important issue is usually how striatal progenitors are developmentally specified into these two unique neuronal populations. In the present study, we characterized the function of Islet-1 (Isl1), a LIM-homeodomain transcription factor, in striatal development. Genetic fate mapping showed that Isl1+progeny specifically developed into a subpopulation of striatonigral neurons that transiently expressed Isl1. InNestin-Cre;Isl1f/fKO mouse brain, differentiation of Dexmedetomidine HCl striatonigral neurons was defective, as evidenced by decreased expression of striatonigral-enriched genes, includingsubstance P,prodynorphin,solute carrier family 35, member D3(Slc35d3), andPlexinD1. Striatonigral axonal projections were also impaired, and abnormal apoptosis was observed inIsl1KO striatum. It was of particular interest that striatopallidal-enriched genes, includingdopamine D2 receptor(Drd2),proenkephalin,A2A adenosine receptor(A2aR) andG protein-coupled receptor 6(Gpr6), were concomitantly up-regulated inIsl1mutant striatum, suggesting derepression of striatopallidal genes in striatonigral neurons in the absence ofIsl1. The suppression of striatopallidal genes byIsl1was further examined by overexpression ofIsl1in the striatum ofDrd2-EGFPtransgenic mice using in utero electroporation. EctopicIsl1expression was sufficient to repressDrd2-EGFP signals in striatopallidal neurons. Taken together, our study suggests thatIsl1specifies the cell fate of striatonigral neurons not only by orchestrating survival, differentiation, and axonal projections of striatonigral neurons but also by suppressing striatopallidal-enriched genes. The dual action of developmental control byIsl1in promoting appropriate striatonigral but repressing improper striatopallidal genetic profiles may make sure sharpening of the striatonigral identity during development. The striatum is the major input structure of basal ganglia circuits (1,2). The striatum comprises medium-sized spiny projection neurons (MSNs) and aspiny interneurons. You will find two populations of MSNs: striatonigral projection neurons of the direct pathway and striatopallidal projection neurons of the indirect pathway (13). These two neuronal populations are intermixed within the striatum without the laminar structure. The striatonigral neurons express dopamine D1 receptor (Drd1a) and material P (SP), and they project their axons to the entopeduncular nucleus and the substantia nigra (SN). The striatopallidal neurons express dopamine D2 receptor (Drd2) and proenkephalin (Penk), and project Dexmedetomidine HCl their axons to the external segment of the globus pallidus (GP). Previous studies using FACS-array and translating ribosome affinity purification (TRAP) approaches have further characterized differential gene expression profiles in striatonigral and striatopallidal populations in postnatal striatum (4,5). At the functional level, direct and indirect pathways are functionally opposed in controlling movement in basal ganglia circuits. The imbalanced activity of these two pathways results in movement disorders, such as Parkinson disease (2,3). Recent study further indicates that direct striatonigral and indirect striatopallidal pathways play unique roles in control of incentive and aversive behaviors, respectively (6). Despite the well-characterized functional differences between the striatonigral and striatopallidal pathways in basal ganglia circuits, the molecular specification of striatonigral and striatopallidal neurons during development remains largely elusive. The LIM homeodomain protein Islet-1 (Isl1) was originally identified as a transcription factor that binds to the islet cell-specific enhancer element in the insulin gene (7). Previous studies have indicated an important role ofIsl1in neuronal development. Null mutation ofIsl1results in cell death and/or Rabbit polyclonal to ARG2 defective differentiation of motor neurons and interneurons in the spinal cord (8,9); bipolar, ganglionic, and amacrine cells in the retina (1012); sensory nociceptive neurons in the dorsal root ganglia; and cholinergic neurons in the basal forebrain (13,14).Isl1is therefore engaged in genetic programs for controlling cell survival and differentiation of various cell types in the nervous system. We and other groups have previously reported that Isl1 is usually transiently expressed in embryonic Dexmedetomidine HCl striatum and is down-regulated after birth, except.