Apical Abscission and Periventricular Heterotopia: A common basis for disease

心尖脱落和脑室周围异位：疾病的共同基础

基本信息

批准号：
9220856
负责人：
RUSSELL JAMES FERLAND
金额：
$ 36.31万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9220856
关键词：
ADP-Ribosylation Factors Actins Adipocytes Affect Anatomy Apical Architecture Binding Binding Proteins Biological Process Brain Cadherins Cell Adhesion Cell Polarity Cell membrane Cells Cilia Cortical Malformation Data Defect Development Disease Distant Down-Regulation Dyslexia Electroporation Embryo Endocytosis Engineering Epithelial Epithelial Cells Excision FLNA gene Genes Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Human Impairment Knockout Mice Lead Maintenance Malignant - descriptor Malignant Neoplasms Mediating Membrane Mesenchymal Microscopy Mitotic Modeling Molecular Mus N-Cadherin Neurons P-Cadherin Phenotype Phosphorylation Process Proliferating Proteins R-cadherin Regulation Role SHH gene Seizures Signal Transduction Site Slice Techniques Testing Thinness Tissues Ventricular Vesicle Work alpha Actin apical membrane body position body system cell motility cilium biogenesis filamin in utero insight kinetosome lateral line lateral ventricle migration neocortical nerve stem cell neuroepithelium novel overexpression periventricular heterotopia progenitor public health relevance relating to nervous system smoothened signaling pathway trafficking

项目摘要

DESCRIPTION (provided by applicant): Apical abscission (AA) describes a recently observed process whereby neuroepithelal cells detach from the ventricular lining of the cortex, leaving an abscissed fragment at the apical membrane and releasing a newly formed migratory neuron/ intermediate progenitor to migrate into the cortical plate. This step is required for neuronal proliferation, initial migration from the ventricular zone, and maintenance of tissue architecture along the neuroependyma. Disruption of this process contributes to periventricular heterotopia (PH), a malformation of cortical development characterized by a smaller brain (impaired proliferation), abnormal neurons clustered deep in the brain along the lateral ventricles (failed migration) and loss in neuroependymal integrity (lost tissue architecture). The mechanisms that govern AA are not known. Given the shared features between AA in normal development and PH in disease, we hypothesize that genes causal for PH regulate AA. We have identified several genes causal for PH, including the actin binding Filamin A (FLNA) and vesicle trafficking associated ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes. In our preliminary data, we have identified a novel FlnA binding protein, Fmn2, which has been implicated in both actin regulation and endosomal trafficking. Disruption of Fmn2 causes the same defects in neocortical brain development in mice, similar to that seen with loss of FlnA and Big2. We have engineered Fmn2 knockout mice and Fmn2-FlnA double knockout mice, as well as developed techniques for transient over-expression/ inhibition of these various genes by in utero electroporation. In Aim1, we will determine what steps in AA (timing, cell polarity, cell fat, cell adhesion, actin) are affected by disruption of PH genes using wide field timed lapse microscopy on ex-vivo embryo slice cultures from knockout mice and following in utero electroporation. In Aim2, we will investigate step-wise interactions between the various PH genes in regulation of AA, through in utero electroporation of various PH gene constructs in constitutively active/inactive states or following over- expression/ inhibition. In Aim3, we will examine whether the proliferative changes seen following disruption of PH associated genes is a result of impaired AA.

描述（由适用提供）：根尖脱落（AA）描述了一个最近观察到的过程，通过该过程，神经上皮细胞从皮质的心室内膜脱离，在顶部膜上留下了脱落的碎片，并释放出新形成的迁移性神经元/中间体，以迁移到皮质板中。此步骤是神经元增殖，从心室区域的初始迁移以及沿神经依赖性组织的组织结构所必需的。该过程的破坏有助于周围性异位症（pH），其特征是以较小的大脑（增殖受损）为特征的皮质发育的畸形，异常的神经元沿着横向心室的深处凝聚在大脑深处（失败的迁移）（失败）和神经依赖性依赖性综合性（失去的迁移）（失去的组织结构）。尚不清楚管理AA的机制。鉴于AA在正常发育中的共同特征与疾病中的pH值之间的共同特征，我们假设该pH调节AA的基因。我们已经确定了pH的几种基因，包括肌动蛋白结合丝蛋白A（FLNA）和囊泡运输相关的ADP-核糖基化因子鸟嘌呤交换因子2（ARFGEF2）基因。在我们的初步数据中，我们已经确定了一种新型的FLNA结合蛋白FMN2，该蛋白在肌动蛋白调节和内体运输中均隐含。 FMN2的破坏会导致小鼠新皮质脑发育的相同缺陷，类似于FLNA和BIG2的丢失。我们已经设计了FMN2敲除小鼠和FMN2-FLNA双基因敲除小鼠，以及开发的技术，用于通过子宫电穿孔中的瞬时过表达/抑制这些各种基因。在AIM1中，我们将确定AA（定时，细胞极性，细胞脂肪，细胞粘合剂，肌动蛋白）中的哪些步骤受到pH基因的破坏，并使用宽场定时失气显微镜从敲除小鼠和子宫电穿孔中的。在AIM2中，我们将通过在组成性活性/非活动状态中的各种pH基因构建体的子宫电穿孔或遵循过表达/抑制作用的各种pH基因构建体中的各种pH基因之间的逐步相互作用。在AIM3中，我们将检查增殖变化是否参见pH相关基因的破坏是AA受损的结果。