人类RFX6在原始肠道管阶段调节内皮的模式
Toshihiro Nakamura1, Junji Fujikura1, Ryo Ito1,2
1Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
PNAS nexus
|January 19, 2024
概括
转录因子RFX6调节PDX1和CDX2,对前肠后部和后肠中部发育至关重要. 缺少RFX6会损害这些基因,解释米切尔-莱利综合征.
科学领域:
- 发展生物学 发展生物学
- 遗传学 是一个遗传学.
- 干细胞生物学 干细胞生物学
背景情况:
- 米切尔-莱利综合征 (MRS) 涉及新生儿糖尿病,胰腺低成形和肠道形.
- 在MRS的形态缺陷仅限于前肠后部和中肠后肠内皮系.
- 在这些缺陷中RFX6的作用背后的精确机制尚未完全理解.
研究的目的:
- 用人类诱导的多能干细胞 (hiPSCs) 阐明转录因子RFX6在内皮早期发育中的作用.
- 调查RFX6缺乏对关键内皮基因表达和分化过程中的细胞群的影响.
主要方法:
- 产生RFX6异合体和同合体敲击/敲击的hiPSC线路.
- 在体外内皮分化试验.
- 在原始肠道管 (PGT) 阶段对基因表达 (PDX1,CDX2,SOX2) 和细胞群 (GFP+细胞) 的分析.
- 基因表达测序 (CAGE-seq) 的顶部分析,以确定RFX6结合部位.
主要成果:
- 在原始肠道管 (PGT) 阶段,RFX6的表达显著增加.
- 缺少RFX6导致PDX1和CDX2的表达减少,PDX1和CDX2是前肠后部和后肠中部的关键调节者.
- 在RFX6缺乏的高PSC中,PDX1+和CDX2+细胞的数量显著减少.
- 前前标志物SOX2的表达不受RFX6缺乏的影响.
- 发现RFX6与PDX1和CDX2的增强子区域结合,其中含有假定的RFX6结合X盒 motif.
结论:
- 在早期内皮分化过程中,RFX6直接调节ParaHox基因PDX1和CDX2的表达.
- RFX6不会影响SOX2的表达,这表明血统的特定调节.
- 由于早期发育阶段的RFX6功能障碍导致的内皮结构受损,可能是米切尔-莱利综合征观察到的形态病理的基础.
更多相关视频
12:59Three and Four-Dimensional Visualization and Analysis Approaches to Study Vertebrate Axial Elongation and Segmentation
Published on: February 28, 2021
3.7K
06:46Mouse Fetal Whole Intestine Culture System for Ex Vivo Manipulation of Signaling Pathways and Three-dimensional Live Imaging of Villus Development
Published on: September 4, 2014
15.0K
相关概念视频
Gastrulation
57.5K
Gastrulation establishes the three primary tissues of an embryo: the ectoderm, mesoderm, and endoderm. This developmental process relies on a series of intricate cellular movements, which in humans transforms a flat, “bilaminar disc” composed of two cell sheets into a three-tiered structure. In the resulting embryo, the endoderm serves as the bottom layer, and stacked directly above it is the intermediate mesoderm, and then the uppermost ectoderm. Respectively, these tissue strata...
57.5K
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
2.2K
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.2K
Determination
18.5K
During embryogenesis, cells become progressively committed to different fates through a two-step process: specification followed by determination. Specification is demonstrated by removing a segment of an early embryo, “neutrally” culturing the tissue in vitro—for example, in a petri dish with simple medium—and then observing the derivatives. If the cultured region gives rise to cell types that it would normally generate in the embryo, this means that it is specified. In...
18.5K
Role Of Notch Signalling In Intestinal Stem Cell Renewal
2.1K
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.1K
Neurulation
41.9K
Neurulation is the embryological process which forms the precursors of the central nervous system and occurs after gastrulation has established the three primary cell layers of the embryo: ectoderm, mesoderm, and endoderm. In humans, the majority of this system is formed via primary neurulation, in which the central portion of the ectoderm—originally appearing as a flat sheet of cells—folds upwards and inwards, sealing off to form a hollow neural tube. As development proceeds, the...
41.9K
