España-Serrano Laura, Guerra Martín-Palanco Noelia, Montero-Pedrazuela Ana, Pérez-Santamarina Estela, Vidal Rebeca, García-Consuegra Inés, Valdizán Elsa María, Pazos Angel, Palomo Tomás, Jiménez-Arriero Miguel Ángel, Guadaño-Ferraz Ana, Hoenicka Janet
Laboratory of Neurosciences, Psychiatry Department, Instituto de Investigación Sanitaria del Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Spain.
Cereb Cortex. 2017 May 1;27(5):2809-2819. doi: 10.1093/cercor/bhw129.
TaqIA is a polymorphism associated with addictions and dopamine-related traits. It is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) nearby the gene for the dopamine D2 receptor (D2R). Since ANKK1 function is unknown, TaqIA-associated traits have been explained only by differences in D2R. Here we report ANKK1 studies in mouse and human brain using quantitative real-time PCR, Western blot, immunohistochemistry, and flow cytometry. ANKK1 mRNA and protein isoforms vary along neurodevelopment in the human and mouse brain. In mouse adult brain ANKK1 is located in astrocytes, nuclei of postmitotic neurons and neural precursors from neurogenic niches. In both embryos and adults, nuclei of neural precursors show significant variation of ANKK1 intensity. We demonstrate a correlation between ANKK1 and the cell cycle. Cell synchronization experiments showed a significant increment of ANKK1-kinase in mitotic cells while ANKK1-kinase overexpression affects G1 and M phase that were found to be modulated by ANKK1 alleles and apomorphine treatment. Furthermore, during embryonic neurogenesis ANKK1 was expressed in slow-dividing neuroblasts and rapidly dividing precursors which are mitotic cells. These results suggest a role of ANKK1 during the cell cycle in neural precursors thus providing biological support to brain structure involvement in the TaqIA-associated phenotypes.
TaqIA是一种与成瘾及多巴胺相关性状有关的多态性。它位于多巴胺D2受体（D2R）基因附近的锚蛋白重复序列和激酶结构域包含1基因（ANKK1）中。由于ANKK1的功能未知，TaqIA相关性状仅通过D2R的差异来解释。在此，我们报告了使用定量实时PCR、蛋白质免疫印迹、免疫组织化学和流式细胞术对小鼠和人类大脑进行的ANKK1研究。ANKK1 mRNA和蛋白质异构体在人类和小鼠大脑的神经发育过程中有所不同。在小鼠成年大脑中，ANKK1位于星形胶质细胞、有丝分裂后神经元的细胞核以及神经源性龛中的神经前体细胞中。在胚胎和成年个体中，神经前体细胞的细胞核均显示出ANKK1强度的显著差异。我们证明了ANKK1与细胞周期之间的相关性。细胞同步化实验表明，有丝分裂细胞中ANKK1激酶显著增加，而ANKK1激酶的过表达会影响G1期和M期，发现这两个时期受ANKK1等位基因和阿扑吗啡处理的调节。此外，在胚胎神经发生过程中，ANKK1在分裂缓慢的神经母细胞和快速分裂的前体细胞（即有丝分裂细胞）中表达。这些结果表明ANKK1在神经前体细胞周期中发挥作用，从而为大脑结构参与TaqIA相关表型提供了生物学支持。
