The ciliogenic transcription factor RFX3 regulates early midline distribution of guidepost neurons required for corpus callosum development.
The ciliogenic transcription factor RFX3 regulates early midline distribution of guidepost neurons required for corpus callosum development.
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DOI：
10.1371/journal.pgen.1002606
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Durand B
中科院分区：
文献类型：
--
作者：
Benadiba C;Magnani D;Niquille M;Morlé L;Valloton D;Nawabi H;Ait-Lounis A;Otsmane B;Reith W;Theil T;Hornung JP;Lebrand C;Durand B
胼胝体（CC）是连接大脑半球的主要连合。CC的再生与人类纤毛病变有关，但这种默认的起源尚不清楚。调节因子X3（RFX3）是参与纤毛发生控制的转录因子，并且Rfx3缺陷小鼠显示纤毛病的几个标志，包括左右不对称缺陷和脑积水。在这里，我们表明，Rfx3缺陷小鼠患有CC发育不全与轴突寻路所需的跨越中线的路标神经元显着紊乱。使用移植试验，我们表明，异常的突变中线区域是CC畸形的主要原因。有条件的基因失活表明RFX3是不需要在路标细胞适当CC的形成，但需要在E12.5前的皮质隔边界的适当图案，因此在后期阶段的路标神经元的准确分布。我们观察到成纤维细胞生长因子8（Fgf 8）在喙连合板的集中但一致的异位表达，与胶质瘤相关癌基因家族锌指3（GLI 3）阻遏物与激活物形式的比例降低有关。我们证明，在脑外植体培养，异位FGF8再现路标神经元缺陷观察到的Rfx3突变体。这项研究揭示了RFX3在早期脑发育过程中的关键作用，通过间接调节GLI3活性，导致FGF8上调，并最终干扰CC形态发生所需的路标神经元的分布。因此，RFX3突变小鼠模型带来了新的理解的机制，在纤毛疾病的CC发育不全。胼胝体是连接哺乳动物两个大脑半球的主要脑连合。胼胝体缺失或减少是人类出生时观察到的最常见的脑畸形，并导致认知和行为缺陷。胼胝体发育不全经常在纤毛病中观察到，这是一组由于纤毛组装或功能缺陷而引起的人类疾病。然而，在这些综合征中这种脑畸形的细胞起源仍然难以捉摸。RFX3转录因子是小鼠纤毛发生的关键调节因子。在这里，我们表明，Rfx3突变小鼠显示胼胝体形成受损。通过移植实验，我们证明，这是由于有缺陷的分布在两个半球之间的一个短暂的神经元群体（路标神经元）所需的路由胼胝体轴突。我们表明，这种异常分布是由于改变了FGF8信号在大脑发育的早期阶段。我们的观察结果表明，小，但集中的信号缺陷，导致特定的路标神经元的分布改变负责胼胝体发育不全。
The corpus callosum (CC) is the major commissure that bridges the cerebral hemispheres. Agenesis of the CC is associated with human ciliopathies, but the origin of this default is unclear. Regulatory Factor X3 (RFX3) is a transcription factor involved in the control of ciliogenesis, and Rfx3–deficient mice show several hallmarks of ciliopathies including left–right asymmetry defects and hydrocephalus. Here we show that Rfx3–deficient mice suffer from CC agenesis associated with a marked disorganisation of guidepost neurons required for axon pathfinding across the midline. Using transplantation assays, we demonstrate that abnormalities of the mutant midline region are primarily responsible for the CC malformation. Conditional genetic inactivation shows that RFX3 is not required in guidepost cells for proper CC formation, but is required before E12.5 for proper patterning of the cortical septal boundary and hence accurate distribution of guidepost neurons at later stages. We observe focused but consistent ectopic expression of Fibroblast growth factor 8 (Fgf8) at the rostro commissural plate associated with a reduced ratio of GLIoma-associated oncogene family zinc finger 3 (GLI3) repressor to activator forms. We demonstrate on brain explant cultures that ectopic FGF8 reproduces the guidepost neuronal defects observed in Rfx3 mutants. This study unravels a crucial role of RFX3 during early brain development by indirectly regulating GLI3 activity, which leads to FGF8 upregulation and ultimately to disturbed distribution of guidepost neurons required for CC morphogenesis. Hence, the RFX3 mutant mouse model brings novel understandings of the mechanisms that underlie CC agenesis in ciliopathies. The Corpus Callosum is the major brain commissure that links the two cerebral hemispheres in mammals. Absence or reduction of the corpus callosum is the most frequent brain malformation observed at birth in humans and leads to cognitive and behavioural deficits. Agenesis of the Corpus Callosum is frequently observed in ciliopathies, a group of human diseases due to defects in cilia assembly or function. However, the cellular origin of this brain malformation in these syndromes remains elusive. RFX3 transcription factor is a key regulator of ciliogenesis in mouse. Here, we show that the Rfx3 mutant mouse shows impaired Corpus Callosum formation. By transplantation experiments, we demonstrate that this is due to defective distribution between the two hemispheres of a transient neuronal population (guidepost neurons) required for routing callosal axons. We show that this abnormal distribution is due to altered FGF8 signalling at early stages of brain development. Our observations show that small but focused signalling defects resulting in specific alterations in the distribution of guidepost neurons are responsible for corpus callosum agenesis.
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