Foxp1 regulation of neonatal vocalizations via cortical development.
Foxp1 regulation of neonatal vocalizations via cortical development.
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DOI：
10.1101/gad.305037.117
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发表时间：
2017-10-15
影响因子：
10.5
通讯作者：
Konopka G
中科院分区：
文献类型：
--
作者：
Usui N;Araujo DJ;Kulkarni A;Co M;Ellegood J;Harper M;Toriumi K;Lerch JP;Konopka G
臼井等人。研究表明，发育中前脑中 Foxp1 的缺失会导致新生儿发声受损以及通过神经元定位和迁移引起的新皮质细胞结构改变。 Foxp1 的 Sumoylation 影响发育中的新皮质中的神经元分化和迁移。自闭症谱系障碍 (ASD) 中驱动大脑发育处于危险之中的分子机制仍然大多未知。先前的研究表明转录因子 FOXP1 与大脑发育和 ASD 病理生理学有关。然而，FOXP1 上游和下游的具体分子途径尚不完全清楚。为了阐明 FOXP1 介导的信号传导对大脑发育，特别是新皮质发育的贡献，我们培育了前脑特异性 Foxp1 条件敲除小鼠。我们发现，发育中前脑中 Foxp1 的缺失会导致新生儿发声受损以及通过神经元定位和迁移导致新皮质细胞结构的改变。使用基因组学方法，我们确定了发育中的新皮质中由 Foxp1 调节的转录网络，并发现此类网络富含参与神经发生和神经元迁移的下游靶标。我们还通过证明胚胎大脑发育过程中 Foxp1 的苏酰化对于介导 Foxp1 和 NuRD 复合物之间的适当相互作用是必要的，揭示了 Foxp1 功能的机制。此外，我们证明 Foxp1 的 sumoylation 影响发育中的新皮质的神经元分化和迁移。总之，这些数据为 FOXP1 在发育中的新皮质中的功能提供了关键的机制见解，并可能揭示 ASD 中存在风险的分子途径。
Usui et al. show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
16.6
作者：
Damiani D;Goffinet AM;Alberts A;Tissir F
通讯作者：
Tissir F
影响因子：
16
作者：
Bossis, G;Melchior, F
通讯作者：
Melchior, F
影响因子：
2.5
作者：
Arriaga, Gustavo;Jarvis, Erich D.
通讯作者：
Jarvis, Erich D.
影响因子：
5.7
作者：
de Guzman, A. Elizabeth;Wong, Michael D.;Nieman, Brian J.
通讯作者：
Nieman, Brian J.