Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1
Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1
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DOI：
10.1523/jneurosci.0777-15.2015
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发表时间：
2015-09-30
影响因子：
5.3
通讯作者：
Schuurmans, Carol
中科院分区：
文献类型：
--
作者：
Adnani, Lata;Langevin, Lisa Marie;Schuurmans, Carol
印记基因是剂量敏感性的，并且它们的失调表达与生长和增殖障碍有关，包括胎儿和出生后生长受限。生长障碍的常见后遗症包括神经发育缺陷，其中一些与胎盘功能不全间接相关。然而，一些与生长相关的印记基因也在胚胎中枢神经系统中表达，它们的异常表达可能更直接地影响神经发育。为了测试生长相关基因是否影响神经谱系进展，我们专注于母系印记基因Zac1。在人类中，ZAC1表达的丧失或获得与生长速度降低和智力残疾有关。为了测试Zac1表达的增加是否直接干扰神经发育，我们在小鼠新皮质祖细胞中错误表达Zac1。效果是惊人的：Zac1延迟了顶端放射状胶质细胞向基底中间神经元祖细胞的过渡，并推迟了它们随后向神经元的分化。Zac1的错误表达也阻止了神经元迁移，与Zac1过表达的神经元暂停更频繁，形成更少的轴突分支在此期间，迁移的神经元进行动态形态转变。类似的，虽然不太引人注目，神经元迁移和形态缺陷观察Zac1敲低，表明Zac1水平必须精确调节。最后，Zac1通过调节Pac1转录来控制神经元迁移，Pac1是神经肽垂体腺苷酸环化酶激活多肽（PACAP）的受体。Pac1和Zac1功能丧失和获得表现为表型，Pac1的过表达挽救了Zac1敲低的神经元迁移表型。因此，Zac1表达失调对新皮层发育具有显著影响，表明在某些生长障碍中这种转录因子在大脑中的错误表达可能导致神经认知缺陷。
Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss-and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits.