Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Neuroscience. 2013 Feb 12;231:282-95. doi: 10.1016/j.neuroscience.2012.11.049. Epub 2012 Dec 5.
Loss of function mutations in THAP1 has been associated with primary generalized and focal dystonia in children and adults. THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and plays a critical role in G(1)-S cell cycle control. Current thinking suggests that dystonia may be a neurodevelopmental circuit disorder. Hence, THAP1 may participate in the development of the nervous system. Herein, we report the neurodevelopmental expression patterns of Thap1 transcript and THAP1 protein from the early postnatal period through adulthood in the rat brain, spinal cord and dorsal root ganglia (DRG). We detected Thap1 transcript and THAP1-immunoreactivity (IR) in the cerebral cortex, cerebellum, striatum, substantia nigra, thalamus, spinal cord and DRG. Thap1 transcript expression was higher in the brain than in spinal cord and DRG at P1 and P7 and declined to similar levels at P14 and later time points in all regions except the cerebellum, where it remained high through adulthood. In the brain, THAP1 expression was highest in early development, particularly in the cerebellum at P7. In addition to Purkinje cells in the cerebellum, THAP1-IR was also localized to pyramidal neurons in the cerebral cortex, relay neurons in the thalamus, medium spiny and cholinergic neurons in the striatum, dopaminergic neurons in the substantia nigra, and pyramidal and interneurons in the hippocampus. In the cerebellar cortex, THAP1-IR was prominently distributed in the perikarya and proximal dendrites of Purkinje cells at early time-points. In contrast, it was more diffusely distributed throughout the dendritic arbor of adult Purkinje cells producing a moderate diffuse staining pattern in the molecular layer. At all time points, nuclear IR was weaker than cytoplasmic IR. The prominent cytoplasmic and developmentally regulated expression of THAP1 suggests that THAP1 may function as part of a cell surface-nucleus signaling cascade involved in terminal neural differentiation.
THAP1 的功能丧失突变与儿童和成人的原发性全身性和局灶性肌张力障碍有关。THAP1 编码一种转录因子（THAP1），它具有非典型的锌指结构域，在 G1-S 细胞周期控制中发挥关键作用。目前的观点认为，肌张力障碍可能是一种神经发育回路障碍。因此，THAP1 可能参与神经系统的发育。在此，我们报告了大鼠大脑、脊髓和背根神经节（DRG）从出生后早期到成年期 THAP1 转录本和 THAP1 蛋白的神经发育表达模式。我们在大脑皮层、小脑、纹状体、黑质、丘脑、脊髓和 DRG 中检测到 Thap1 转录本和 THAP1-免疫反应性（IR）。在 P1 和 P7 时，大脑中的 Thap1 转录本表达高于脊髓和 DRG，而在所有区域（小脑除外），其表达在 P14 及以后的时间点下降到相似水平，而小脑在成年期仍保持高水平。在大脑中，THAP1 的表达在早期发育中最高，尤其是在 P7 时的小脑。除了小脑的浦肯野细胞外，THAP1-IR 还定位于大脑皮层的锥体神经元、丘脑的中继神经元、纹状体的中型多棘神经元和胆碱能神经元、黑质中的多巴胺能神经元以及海马体的锥体神经元和中间神经元。在小脑皮质中，THAP1-IR 在早期主要分布在浦肯野细胞的胞体和近端树突中。相比之下，在成年浦肯野细胞的树突中分布更为弥散，在分子层产生中度弥散的染色模式。在所有时间点，核 IR 均弱于胞质 IR。THAP1 的显著胞质表达和发育调控表明，THAP1 可能作为参与终末神经分化的细胞表面-核信号级联反应的一部分发挥作用。
