Identification of two novel Shank3 transcripts in the developing mouse neocortex
Identification of two novel Shank3 transcripts in the developing mouse neocortex
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DOI：
10.1111/jnc.12505
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发表时间：
2014-01-01
影响因子：
4.7
通讯作者：
Uchino, Shigeo
中科院分区：
文献类型：
--
作者：
Waga, Chikako;Asano, Hirotsugu;Uchino, Shigeo
SHANK 3是在兴奋性突触的突触后密度中富集的突触支架蛋白。由于在自闭症谱系障碍（ASD）患者的特定表型组中已经鉴定出几种SHANK 3突变，因此强烈怀疑SHANK 3参与ASD的发病机制和神经病理学。已知几种SHANK 3亚型在发育中的大脑中产生，但尚未对其进行充分研究。在这里，我们确定了两个不同的氨基末端截短的Shank 3转录。一种转录物，命名为Shank 3c-3，产生含有整个羧基末端的同种型，但另一种转录物，命名为Shank 3c-4，产生羧基末端截短的同种型。在发育过程中，新的Shank 3转录本的表达在出生后增加，在P14时短暂下降，然后在此后再次逐渐增加。我们还确定，甲基CpG结合蛋白2（MeCP 2）参与调节新的Shank 3转录本的表达。MeCP 2是一种转录调节因子，已被鉴定为Rett综合征的致病分子，Rett综合征是一种包括自闭症行为的神经发育障碍。我们证明了野生型小鼠和Mecp 2缺陷小鼠中新型Shank 3转录本的表达之间的差异。这些发现表明SHANK 3亚型可能与Rett综合征的突触异常有关。
SHANK3 is a synaptic scaffolding protein enriched in the post-synaptic density of excitatory synapses. Since several SHANK3 mutations have been identified in a particular phenotypic group of patients with autism spectrum disorder (ASD), SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Several SHANK3 isoforms are known to be produced in the developing brain, but they have not been fully investigated. Here, we identified two different amino-terminus truncated Shank3 transcripts. One transcript, designated as Shank3c-3, produces an isoform that contains the entire carboxyl-terminus, but the other transcript, designated as Shank3c-4, produces a carboxyl-terminus truncated isoform. During development, expression of the novel Shank3 transcripts increased after birth, transiently decreased at P14 and then gradually increased again thereafter. We also determined that methyl CpG-binding protein 2 (MeCP2) is involved in regulating expression of the novel Shank3 transcripts. MeCP2 is a transcriptional regulator that has been identified as the causative molecule of Rett syndrome, a neurodevelopmental disorder that includes autistic behavior. We demonstrated a difference between the expression of the novel Shank3 transcripts in wild-type mice and Mecp2-deficient mice. These findings suggest that the SHANK3 isoforms may be implicated in the synaptic abnormality in Rett syndrome.