Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect
Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect
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DOI：
10.1111/j.1460-9568.2009.06754.x
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发表时间：
2009-05-01
影响因子：
3.4
通讯作者：
Kataoka, Tohru
中科院分区：
文献类型：
--
作者：
Bilasy, Shymaa E.;Satoh, Takaya;Kataoka, Tohru
神经迁移缺陷导致各种类型的人类皮质发育畸形，包括皮质下带状异位，其显示在初级皮质下形成次级皮质板，并且通常由DCX（doublecortin）基因突变引起。皮质下带状异位常与智力低下和癫痫有关。我们以前发现RA-GEF-1作为Rap 1小GTdR的鸟嘌呤核苷酸交换因子（GEF）。在这里，我们已经分析了其在体内的作用，在成年大脑皮层的形成，通过使用端脑特异性RA-GEF-1条件性敲除（cKO）小鼠，产生交配RA-GEF-1（flox/flox）小鼠与Emx 1-cre敲入小鼠。RA-GEF-1 cKO小鼠在其脑结构中显示出严重的缺陷，包括相对正常皮质下的异位皮质肿块。异位皮质肿块缺乏正常的六层分层，但保留皮质下的连接显示逆行追踪。此外，RA-GEF-1 cKO小鼠表现出诱导癫痫发作的较低阈值。这些表型与人类皮质下带状异位症的表型相似。此外，cKO小鼠的前连合、背侧海马连合、胼胝体发育不全，侧脑室扩大。我们的研究结果表明RA-GEF-1在神经迁移中的重要功能。
Neural migration defects lead to various types of human malformations of cortical development including subcortical band heterotopia, which shows formation of a secondary cortical plate beneath the primary cortex and is typically caused by mutation of the DCX (doublecortin) gene. Subcortical band heterotopia is usually associated with mental retardation and epilepsy. We previously discovered RA-GEF-1 as a guanine nucleotide exchange factor (GEF) for Rap1 small GTPase. Here we have analysed its in-vivo role in formation of the adult cerebral cortex by using telencephalon-specific RA-GEF-1 conditional knockout (cKO) mice, generated by mating RA-GEF-1(flox/flox) mice with Emx1-cre knockin mice. RA-GEF-1 cKO mice showed severe defects in their brain structures including an ectopic cortical mass underlying a relatively normal cortex. The ectopic cortical mass lacked the normal six-layered lamination but preserved the subcortical connectivity as revealed by retrograde tracing. Further, RA-GEF-1 cKO mice exhibited a lower threshold for the induction of epileptic seizures. These phenotypes have a resemblance to those of human subcortical band heterotopia. In addition, the agenesis of anterior commissures, the dorsal hippocampus commissure, the corpus callosum and the enlargement of the lateral ventricles were observed in cKO mice. Our findings suggest a crucial function of RA-GEF-1 in neural migration.