Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, France.
Neurobiol Dis. 2012 Apr;46(1):190-203. doi: 10.1016/j.nbd.2012.01.007. Epub 2012 Jan 26.
Copy number variation in a small region of chromosome 21 containing DYRK1A produces morphological and cognitive alterations in human. In mouse models, haploinsufficiency results in microcephaly, and a human DYRK1A gain-of-function model (three alleles) exhibits increased brain volume. To investigate these developmental aspects, we used a murine BAC clone containing the entire gene to construct an overexpression model driven by endogenous regulatory sequences. We compared this new model to two other mouse models with three copies of Dyrk1a, YACtgDyrk1a and Ts65Dn, as well as the loss-of-function model with one copy (Dyrk1a(+/-)). Growth, viability, brain weight, and brain volume depended strongly upon gene copy number. Brain region-specific variations observed in gain-of-function models mirror their counterparts in the loss-of-function model. Some variations, such as increased volume of the superior colliculus and ventricles, were observed in both the BAC transgenic and Ts65Dn mice. Using unbiased stereology we found that, in the cortex, neuron density is inversely related to Dyrk1a copy number but, in thalamic nuclei, neuron density is directly related to copy number. In addition, six genes involved either in cell division (Ccnd1 and pAkt) or in neuronal machinery (Gap43, Map2, Syp, Snap25) were regulated by Dyrk1a throughout development, from birth to adult. These results imply that Dyrk1a expression alters different cellular processes during brain development. Dyrk1a, then, has two roles in the development process: shaping the brain and controlling the structure of neuronal components.
染色体 21 上包含 DYRK1A 的小区域的拷贝数变异会导致人类的形态和认知改变。在小鼠模型中，杂合不足导致小头畸形，而人类 DYRK1A 功能获得模型（三个等位基因）表现出脑体积增加。为了研究这些发育方面，我们使用含有整个基因的小鼠 BAC 克隆，构建了一个由内源性调节序列驱动的过表达模型。我们将这个新模型与其他两个具有三个 Dyrk1a 拷贝的小鼠模型（YACtgDyrk1a 和 Ts65Dn）以及一个具有一个拷贝（Dyrk1a(+/-)）的功能丧失模型进行了比较。生长、活力、脑重和脑体积强烈依赖于基因拷贝数。在功能获得模型中观察到的脑区特异性变化反映了其在功能丧失模型中的对应变化。在 BAC 转基因和 Ts65Dn 小鼠中观察到一些变化，如上丘和脑室体积增加。使用无偏立体学，我们发现，在外皮质，神经元密度与 Dyrk1a 拷贝数呈负相关，但在丘脑核中，神经元密度与拷贝数呈正相关。此外，六个涉及细胞分裂（Ccnd1 和 pAkt）或神经元机制（Gap43、Map2、Syp、Snap25）的基因在大脑发育过程中（从出生到成年）均受 Dyrk1a 调控。这些结果表明，在大脑发育过程中，Dyrk1a 表达改变了不同的细胞过程。因此，Dyrk1a 在发育过程中有两个作用：塑造大脑和控制神经元成分的结构。
