Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

项目总结： 该项目开发了细胞和动物模型，以了解多价转录因子的作用， ZNF423在整合细胞外信号通路和细胞内谱系通路的信息中 后脑发育。ZNF423编码一种结构性核转录调节蛋白， 结合EBF家族的谱系分化因子和转录效应因子进行规范信号传递 途径，包括SMAD，维甲酸，和缺口细胞内结构域。ZNF423突变是 报道在罕见的Joubert综合征(JBTS19)和肾单位(NPHP14)纤毛病患者中。这个 纤毛疾病包括一个广泛的家族，由信号缺陷统一在一起的个别罕见的疾病 初级纤毛。临床表现从轻微到致命，从单个器官的原发受累。 到更具多面性的展示。绝大多数被确定为睫毛疾病的基因 编码初级纤毛的物理成分。控制纤毛依赖的调控基因 改变睫状体缺陷结局的信号和遗传修饰物仍未得到充分研究 在更典型的病例中，关于致病机制和潜在的干预要点。 ZNF423被认为包括几个转录复合体中的一个整合节点，该复合体 大脑发育过程中对经典细胞间信号的反应和对SHH信号的调节 穿过初级纤毛。报道的患者和小鼠模型都显示出后脑畸形 包括蚯蚓发育不全或发育不全。AIM 1将测试ZNF423活性的假设 将来自复杂信号环境的信息转化为可预测的细胞响应。目标2将 全面测试在体外改变细胞结果的修饰基因，以响应丢失的 ZNF423。AIM 3将测试ZNF423参与少基因脑畸形的假说 经过充分验证的动物模型。

Project Summary: This project develops cell and animal models to understand the role of a multivalent transcription factor, ZNF423, in integrating information from extracellular signaling and intracellular lineage pathways during hindbrain development. ZNF423 encodes a constitutively nuclear transcriptional regulatory protein that binds lineage differentiation factors of the EBF family and transcriptional effectors for canonical signling pathways, including SMAD, retinoic acid, and NOTCH intracellular domains. ZNF423 mutations are reported in rare Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) ciliopathy patients. The ciliopathies comprise a broad family of individually rare disorders unified by signaling defects in primary cilia. Clinical presentations range mild to lethal and from primary involvement of a single organ to more pleiotropic presentations. The overwhelming majority of genes identified for ciliopathy disorders encode physical components of primary cilia. Regulatory genes that control cilium-dependent signaling and genetic modifiers that change the outcome of ciliary defects remain understudied with respect to pathogenic mechanisms and potential points for intervention in more typical cases. ZNF423 is thought to comprise an integrative node among several transcriptional complexes that respond to classical intercellular signals during brain development and to regulate SHH signaling through the primary cilium. Both reported patients and mouse models show hindbrain malformations that include hypoplasia or agenesis of the vermis. Aim 1 will test hypotheses for ZNF423 activity in canalizing information from complex signaling environments into predictable cell responses. Aim 2 will comprehensively test for modifier genes that alter cellular outcomes ex vivo in response to loss of ZNF423. Aim 3 will test hypotheses for ZNF423 participation in oligogenic brain malformations in a well-validated animal model.