Casoni Filippo, Croci Laura, Bosone Camilla, D'Ambrosio Roberta, Badaloni Aurora, Gaudesi Davide, Barili Valeria, Sarna Justyna R, Tessarollo Lino, Cremona Ottavio, Hawkes Richard, Warming Søren, Consalez G Giacomo
Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
Università Vita-Salute San Raffaele, Milan 20132, Italy.
Development. 2017 Oct 15;144(20):3686-3697. doi: 10.1242/dev.155077. Epub 2017 Sep 11.
The gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null mutants develop cerebellar malformations, the underlying mechanism remains unknown. mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies.
该基因编码一种参与关键发育途径的含30个锌指的转录因子。尽管无效突变体出现小脑畸形，但其潜在机制仍不清楚。突变与Joubert综合征相关，Joubert综合征是一种导致小脑蚓部发育不全和共济失调的纤毛病。其参与DNA损伤反应（DDR），这引发了关于其在小脑发育中作为神经祖细胞周期进程调节因子的作用的问题。为了表征ZFP423在神经发生中的功能，我们分析了等位基因小鼠突变体，其中不同的功能域被删除。一种缺失损害有丝分裂纺锤体定向，导致细胞周期过早退出和浦肯野细胞（PC）祖细胞池缺失。另一种缺失损害PC分化。在这两种突变体中，细胞周期进程明显延迟，并且DDR标记物在小脑室管膜区祖细胞中上调。我们的证据揭示了ZFP423在PC祖细胞发育的不同方面所起的结构域特异性作用，同时强化了一个新出现的观点，即DDR受损可能是JS和其他纤毛病发病机制中的关键因素。
