Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities.
Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities.
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Gpr161 缺失后音刺猬信号传导的去抑制揭示了前脑和心室异常。
DOI：
10.1016/j.ydbio.2019.03.011
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发表时间：
2019
影响因子：
2.7
通讯作者：
Mukhopadhyay,Saikat
中科院分区：
文献类型：
--
作者：
Shimada,IsseiS;Somatilaka,BandarigodaN;Hwang,Sun-Hee;Anderson,AshleyG;Shelton,JohnM;Rajaram,Veena;Konopka,Genevieve;Mukhopadhyay,Saikat
转录抑制物的逆梯度拮抗转录效应物对形态原的反应。然而，这种反向调控的作用可能不仅仅是因为缺乏抑制物。Sonic hedgehog(Shh)通过在前脑腹侧表达来形成模式；然而，矛盾的是，缺乏Gli3抑制物的拮抗会导致通路激活不足。有趣的是，由于缺乏主要的纤毛定位的G蛋白偶联受体，GPR161通过协调缺乏Gli3抑制物和平滑非依赖性激活增加了小鼠神经管中的Shh信号。在这里，通过在妊娠早期删除小鼠神经上皮细胞和放射状胶质细胞中的Gpr161，我们检测到整个前脑Shh信号的去抑制，从而能够确定病理生理后果。脑脊液积聚(脑积水)在出生时就很明显了，尽管常见的多纤毛状室管膜细胞或导水管的缺陷并不常见。相反，在胚胎发育过程中，由于放射状胶质细胞过度增殖，脑室表面扩张(脑室增大)。皮质表型包括内侧扣带回多小回，中间前体细胞和基底径向神经胶质细胞增殖增加，新皮质细胞构筑结构改变，上层神经元增多，深层神经元减少。最后，脑室周围结节异位是由于神经元迁移中断所致，而放射状神经胶质支架未受影响。总体而言，在妊娠早期抑制Shh途径可以防止心室过度生长，并调节皮质旋转和新皮质/脑室周围细胞结构。
Inverse gradients of transcriptional repressors antagonize the transcriptional effector response to morphogens. However, the role of such inverse regulation might not manifest solely from lack of repressors. Sonic hedgehog (Shh) patterns the forebrain by being expressed ventrally; however, absence of antagonizing Gli3 repressor paradoxically cause insufficient pathway activation. Interestingly, lack of the primary cilia-localized G-protein-coupled receptor, Gpr161 increases Shh signaling in the mouse neural tube from coordinated lack of Gli3 repressor and Smoothened-independent activation. Here, by deletingGpr161in mouse neuroepithelial cells and radial glia at early mid-gestation we detected derepression of Shh signaling throughout forebrain, allowing determination of the pathophysiological consequences. Accumulation of cerebrospinal fluid (hydrocephalus) was apparent by birth, although usual causative defects in multiciliated ependymal cells or aqueduct were not seen. Rather, the ventricular surface was expanded (ventriculomegaly) during embryogenesis from radial glial overproliferation. Cortical phenotypes included polymicrogyria in the medial cingulate cortex, increased proliferation of intermediate progenitors and basal radial glia, and altered neocortical cytoarchitectonic structure with increased upper layer and decreased deep layer neurons. Finally, periventricular nodular heterotopia resulted from disrupted neuronal migration, while the radial glial scaffold was unaffected. Overall, suppression of Shh pathway during early mid-gestation prevents ventricular overgrowth, and regulates cortical gyration and neocortical/periventricular cytoarchitecture.
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影响因子：
7.3
作者：
Mukhopadhyay S;Rohatgi R
通讯作者：
Rohatgi R
影响因子：
2.7
作者：
Spassky, N.;Han, Y. -G.;Alvarez-Buylla, A.
通讯作者：
Alvarez-Buylla, A.
DOI：
10.1523/jneurosci.4892-10.2011
发表时间：
2011-04-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Wang H;Ge G;Uchida Y;Luu B;Ahn S
通讯作者：
Ahn S
影响因子：
4.6
作者：
K. Shimamura;Dennis J. Hartigan;Salvador Martínez;L. Puelles;J. Rubenstein
通讯作者：
K. Shimamura;Dennis J. Hartigan;Salvador Martínez;L. Puelles;J. Rubenstein
影响因子：
9.8
作者：
Cantagrel, Vincent;Silhavy, Jennifer L.;Gleeson, Joseph G.
通讯作者：
Gleeson, Joseph G.