Segregated expressions of autism risk genes Cdh11 and Cdh9 in autism-relevant regions of developing cerebellum
Segregated expressions of autism risk genes Cdh11 and Cdh9 in autism-relevant regions of developing cerebellum
复制标题
自闭症风险基因 Cdh11 和 Cdh9 在发育小脑自闭症相关区域的分离表达
DOI：
10.1186/s13041-019-0461-4
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发表时间：
2019-05-02
期刊：
影响因子：
3.6
通讯作者：
Yuan，Xiao-Bing
中科院分区：
文献类型：
--
作者：
Wang，Chunlei;Pan，Yi-Hsuan;Yuan，Xiao-Bing
最近的全基因组关联研究（GWAS）和全基因组测序（WGS）的结果强调了II型钙粘蛋白作为自闭症谱系障碍（ASD）的风险基因。为了确定这些钙粘蛋白是否可能与ASD相关脑区的形态发生有关，进行了原位杂交（ISH）实验，以研究两种ASD相关钙粘蛋白Cdh 9和Cdh 11在发育中的小脑中的mRNA表达谱。在出生后的第一周，Cdh 9和Cdh 11在小脑浦肯野细胞的分离亚群中以高水平表达，并且随着发育的进行，这两个基因的表达都下降。Cdh 11的发育表达主要局限于蚓部的背小叶（小叶VI/VII）以及相当于人脑中的脚I和脚II区域的侧半球区域，已知这些区域介导成人的高阶认知功能。此外，在小脑蚓部的小叶VI/VII中，Cdh 9和Cdh 11以互补的模式表达，Cdh 11表达区的两侧是Cdh 9表达区。有趣的是，在小叶VI/VII的中央区域中Cdh 11的高水平表达与浦肯野细胞标志物钙结合蛋白的低水平表达相关，这与同一区域中浦肯野细胞的延迟成熟相一致。这些发现表明，这两个ASD相关的钙粘蛋白可能发挥不同的，但协调的功能，以调节自闭症相关电路在小脑的布线。
Results of recent genome-wide association studies (GWAS) and whole genome sequencing (WGS) highlighted type II cadherins as risk genes for autism spectrum disorders (ASD). To determine whether these cadherins may be linked to the morphogenesis of ASD-relevant brain regions, in situ hybridization (ISH) experiments were carried out to examine the mRNA expression profiles of two ASD-associated cadherins, Cdh9 and Cdh11, in the developing cerebellum. During the first postnatal week, both Cdh9 and Cdh11 were expressed at high levels in segregated sub-populations of Purkinje cells in the cerebellum, and the expression of both genes was declined as development proceeded. Developmental expression of Cdh11 was largely confined to dorsal lobules (lobules VI/VII) of the vermis as well as the lateral hemisphere area equivalent to the Crus I and Crus II areas in human brains, areas known to mediate high order cognitive functions in adults. Moreover, in lobules VI/VII of the vermis, Cdh9 and Cdh11 were expressed in a complementary pattern with the Cdh11-expressing areas flanked by Cdh9-expressing areas. Interestingly, the high level of Cdh11 expression in the central domain of lobules VI/VII was correlated with a low level of expression of the Purkinje cell marker calbindin, coinciding with a delayed maturation of Purkinje cells in the same area. These findings suggest that these two ASD-associated cadherins may exert distinct but coordinated functions to regulate the wiring of ASD-relevant circuits in the cerebellum.