Divisions of Developmental Biology, Neurosurgery, Experimental Hematology and Cancer Biology and Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati OH 45229.
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E4026-35. doi: 10.1073/pnas.1308275110. Epub 2013 Sep 30.
The mammalian striatum controls the output of the basal ganglia via two distinct efferent pathways, the direct (i.e., striatonigral) and the indirect (i.e., striatopallidal) pathways. The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in a subpopulation of striatal progenitors; however, its specific role in striatal development remains unknown. Our genetic fate-mapping results show that Isl1-expressing progenitors give rise to striatal neurons belonging to the striatonigral pathway. Conditional inactivation of Isl1 in the telencephalon resulted in a smaller striatum with fewer striatonigral neurons and reduced projections to the substantia nigra. Additionally, conditional inactivation in the ventral forebrain (including both the telencephalon and diencephalon) revealed a unique role for Isl1 in diencephalic cells bordering the internal capsule for the normal development of the striatonigral pathway involving PlexinD1-Semaphorin 3e (Sema3e) signaling. Finally, Isl1 conditional mutants displayed a hyperlocomotion phenotype, and their locomotor response to psychostimulants was significantly blunted, indicating that the alterations in basal ganglia circuitry contribute to these mutant behaviors.
哺乳动物纹状体通过两条不同的传出通路（即直接通路[即纹状体苍白球]和间接通路[即纹状体黑质]）控制基底神经节的输出。LIM 同源结构域转录因子 Islet1（Isl1）在纹状体祖细胞的一个亚群中表达；然而，其在纹状体发育中的具体作用尚不清楚。我们的遗传命运图谱结果表明，表达 Isl1 的祖细胞产生属于纹状体苍白球通路的纹状体神经元。在端脑中条件性失活 Isl1 导致纹状体变小，纹状体苍白球神经元减少，对黑质的投射减少。此外，在腹侧前脑（包括端脑和间脑）中的条件性失活揭示了 Isl1 在内部胶囊边界的间脑细胞中对于涉及 PlexinD1-神经丝氨酸 3e（Sema3e）信号的纹状体苍白球通路正常发育的独特作用。最后，Isl1 条件性突变体表现出过度运动表型，并且它们对精神兴奋剂的运动反应明显减弱，表明基底神经节回路的改变导致了这些突变体行为。
