BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain.
BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain.
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DOI：
10.1371/journal.pone.0175888
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Harada A
中科院分区：
文献类型：
--
作者：
Teoh JJ;Iwano T;Kunii M;Atik N;Avriyanti E;Yoshimura SI;Moriwaki K;Harada A
BIG 1是小G蛋白Arf的激活蛋白，由Arfgef 1基因编码，是癫痫性脑病的候选基因之一。为了了解BIG 1在癫痫性脑病中的参与，我们分析了BIG 1缺陷小鼠，发现BIG 1在体外和体内调节神经突生长和大脑发育。BIG 1的丢失减少了新皮层和海马的大小。在BIG 1缺陷小鼠中，神经元祖细胞（NPC）和中间神经元不受影响。而Tbr 1+和Ctip 2+神经元则表现出时空依赖性的凋亡。这种凋亡从梨状皮质（PIR）逐渐进展，在新皮质达到高峰，然后从胚胎第13.5天（E13.5）到E17.5进展到海马。在BIG 1缺陷小鼠中，新皮层的上层（UL）和DL顺序得以维持，但兴奋性神经元倾向于在其目的层之前积累。进一步的脉冲追踪迁移试验表明，迁移缺陷是非细胞自主的，继发于E15.5后BIG 1缺陷新皮质的凋亡进展。在BIG 1缺陷小鼠中，我们观察到皮质丘脑轴突从初级体感皮层（S1）到背外侧膝状体核（dLGN）的异位投射。丘脑皮质轴突不能穿过间脑-端脑边界（DTB）。在体外，BIG 1缺陷神经元表现出神经元极化延迟。BIG 1缺陷的神经元也对低剂量谷氨酸（5 μM）高度敏感，并通过凋亡而死亡。这项研究表明BIG 1在发育中的胚胎脑中DL神经元的存活和神经元极性的产生中的作用。
BIG1, an activator protein of the small GTPase, Arf, and encoded by the Arfgef1 gene, is one of candidate genes for epileptic encephalopathy. To know the involvement of BIG1 in epileptic encephalopathy, we analyzed BIG1-deficient mice and found that BIG1 regulates neurite outgrowth and brain development in vitro and in vivo. The loss of BIG1 decreased the size of the neocortex and hippocampus. In BIG1-deficient mice, the neuronal progenitor cells (NPCs) and the interneurons were unaffected. However, Tbr1+ and Ctip2+ deep layer (DL) neurons showed spatial-temporal dependent apoptosis. This apoptosis gradually progressed from the piriform cortex (PIR), peaked in the neocortex, and then progressed into the hippocampus from embryonic day 13.5 (E13.5) to E17.5. The upper layer (UL) and DL order in the neocortex was maintained in BIG1-deficient mice, but the excitatory neurons tended to accumulate before their destination layers. Further pulse-chase migration assay showed that the migration defect was non-cell autonomous and secondary to the progression of apoptosis into the BIG1-deficient neocortex after E15.5. In BIG1-deficient mice, we observed an ectopic projection of corticothalamic axons from the primary somatosensory cortex (S1) into the dorsal lateral geniculate nucleus (dLGN). The thalamocortical axons were unable to cross the diencephalon–telencephalon boundary (DTB). In vitro, BIG1-deficient neurons showed a delay in neuronal polarization. BIG1-deficient neurons were also hypersensitive to low dose glutamate (5 μM), and died via apoptosis. This study showed the role of BIG1 in the survival of DL neurons in developing embryonic brain and in the generation of neuronal polarity.