ZFP423 regulates early patterning and multiciliogenesis in the hindbrain choroid plexus

The choroid plexus (ChP) is a secretory tissue that produces cerebrospinal fluid (CSF) secreted into the ventricular system. It is a monolayer of secretory, multiciliated epithelial cells derived from neuroepithelial progenitors and overlying a stroma of mesenchymal cells of mesodermal origin. Zfp423, encoding a Kruppel-type zinc finger transcription factor essential for cerebellar development and mutated in rare cases of cerebellar vermis hypoplasia / Joubert syndrome and other ciliopathies, is expressed in the hindbrain roof plate (RP), from which the IV ventricleChP arises, and, later, in mesenchymal cells giving rise to the stroma and leptomeninges.Zfp423mutants display a marked reduction of the hindbrain ChP (hChP), which 1) fails to express established markers of its secretory function and genes implicated in its development and maintenance (Lmx1a, Otx2); 2) shows a perturbed expression of signaling pathways previously unexplored in hChP patterning (Wnt3); 3) displays a lack of multiciliated epithelial cells and a profound dysregulation of master genes of multiciliogenesis (Gmnc). Our results propose Zfp423as a master gene and one of the earliest known determinants of hChP development. 3x E9.5 wt hindbrains, 3x E9.5 d28-30 hindbrains, and 3x E9.5 d9-20 hindbrains脉络丛（choroid plexus，ChP）是一类分泌组织，可合成并向脑室系统分泌脑脊液（cerebrospinal fluid，CSF）。其由一层源自神经上皮祖细胞的分泌型多纤毛上皮细胞构成，下方覆盖着中胚层起源的间充质细胞基质。Zfp423编码一种Krüppel型锌指转录因子，对小脑发育至关重要，且在少数小脑蚓部发育不全、Joubert综合征及其他纤毛病病例中发生突变。该基因最初在脑后顶板（hindbrain roof plate，RP）中表达——第四脑室脉络丛即起源于此结构——后续又在构成基质与软脑膜的间充质细胞中表达。Zfp423突变体的后脑脉络丛（hindbrain ChP，hChP）出现显著减少，具体表现为：1）无法表达其分泌功能的既定标志物及参与其发育与维持的基因（Lmx1a、Otx2）；2）此前未在hChP模式建成中被研究的Wnt3信号通路表达异常；3）缺乏多纤毛上皮细胞，且多纤毛发生主控基因（Gmnc）出现严重表达失调。本研究结果表明，Zfp423是调控hChP发育的主控基因之一，也是目前已知的最早的hChP发育决定因子之一。本研究使用的样本包括3例胚胎发育第9.5天（E9.5）野生型（wild type，wt）后脑组织、3例E9.5 d28-30后脑组织及3例E9.5 d9-20后脑组织。