Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

Zfp423 Joubert 综合征及相关疾病的机制

• 批准号: 10620800
• 负责人: BRUCE A HAMILTON
• 金额: $ 55.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620800
• 关键词: Animal Genetics; Animal Model; Animals; Architecture; Binding Proteins; Biological Assay; Brain; CRISPR interference; Cell Lineage; Cell Proliferation; Cell model; Cells; Cerebellar vermis structure; Cilia; Clinical; Complex; Cues; Cytoplasmic Granules; Data; Defect; Development; Differentiation Antigens; Disease; Environment; Family; Frequencies; Gene Modified; Genes; Genetic; Genetic Transcription; Heterozygote; Homozygote; Human; Individual; Intervention; Joubert syndrome; Ligands; Mediating; Modeling; Molecular Genetics; Mus; Mutant Strains Mice; Mutation; Nephronophthisis; Neuronal Differentiation; Nuclear; Organ; Outcome; Pathogenicity; Pathway interactions; Patients; Pattern; Phenotype; Population; Proliferating; Proteins; Rare Diseases; Regulator Genes; Reporting; Reproducibility; Retinoic Acid Receptor; Role; SHH gene; Signal Pathway; Signal Transduction; Structure; Testing; Transcription Regulatory Protein; Tretinoin; Undifferentiated; Variant; Zinc Fingers; brain abnormalities; brain malformation; ciliopathy; developmental disease; developmental neurobiology; extracellular; genetic testing; granule cell; hindbrain; improved; in vivo; innovation; malformation; morphogens; mouse model; mutant; notch protein; precursor cell; progenitor; programs; response; single-cell RNA sequencing; stem cells; tool; transcription factor

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.

项目概要： 该项目开发细胞和动物模型来了解多价转录因子的作用， ZNF423，在整合细胞外信号传导和细胞内谱系途径的信息时 后脑发育。 ZNF423 编码一种组成型核转录调节蛋白， 结合 EBF 家族的谱系分化因子和经典信号转导的转录效应子 途径，包括 SMAD、视黄酸和 NOTCH 细胞内结构域。 ZNF423 突变是 在罕见的 Joubert 综合征 (JBTS19) 和肾结核 (NPHP14) 纤毛病患者中有报道。这 纤毛病包括一系列单独罕见的疾病，这些疾病通过信号缺陷统一起来 初级纤毛。临床表现范围从轻度到致命，从单一器官的主要受累 更多的多效性演示。绝大多数已被鉴定为纤毛病基因 编码初级纤毛的物理成分。控制纤毛依赖性的调节基因 改变纤毛缺陷结果的信号传导和遗传修饰剂仍未得到充分研究 关于更典型病例的致病机制和潜在干预点。 ZNF423 被认为包含多个转录复合物之间的整合节点， 对大脑发育过程中的经典细胞间信号做出反应并调节 SHH 信号传导 通过初级纤毛。报道的患者和小鼠模型均显示后脑畸形 包括蚓部发育不全或发育不全。目标 1 将测试 ZNF423 活性的假设 将复杂信号环境中的信息转化为可预测的细胞反应。目标2将 全面测试修饰基因，这些修饰基因会在体外改变细胞结果，以响应失去 ZNF423。目标 3 将测试 ZNF423 参与寡基因脑畸形的假设 经过充分验证的动物模型。

项目成果

Strain-Dependent Modifier Genes Determine Survival in Zfp423 Mice.

• DOI: 10.1534/g3.120.401720
• 发表时间: 2020-11-05
• 期刊: G3 (Bethesda, Md.)
• 作者: Alcaraz WA;Liu Z;Valdes P;Chen E;Valdovino Gonzalez AG;Wade S;Wong C;Kim E;Chen HM;Ponn A;Concepcion D;Hamilton BA
• 通讯作者: Hamilton BA