MicroRNA的发现使生物学许多领域都向前迈进一大步。研究人员发现,microRNA在心脏细胞的生长及分化过程中,扮演着极其重要的平衡角色。
Gladstone心脏疾病研究所的(GICD)研究人员日前宣布,他们辨认出一个与心脏型态及功能有关的重要遗传因素。根据这篇发表于Cell的研究报告,Deepak Srivastava等人成功地删除了小鼠模型中,一种称为microRNA的遗传因素,以了解miRNA在心血管分化和发育过程中扮演的角色。
MicroRNAs (miRNAs)是一种大小约21—23个碱基的单链小分子RNA,是由具有发夹结构、约70-90个碱基大小的单链RNA前体,经过Dicer酶加工后生成,不同于siRNA,但是和siRNA有密切的关连性。
心脏的发育与许多因素有关,研究人员剔除了负责编码miRNA的基因,以彻底了解miRNA对于心脏发育之复杂过程的贡献。
研究人员调查一种名为miR-1-2的microRNA,这个基因产物在心脏和肌肉组织中大量表现。另外一个与miR-1-2有关的microRNA是miR-1-1,miR-1-1无法补偿缺乏miR-1-2时,对于心脏发育造成的影响。
研究人员发现,当小鼠失去了miR-1-2,心脏功能受到极大的影响,包括心脏的的形态发生和心脏细胞数量的控制。其中半数的小鼠发生的心室穿孔,而心室穿孔是最常见的人类先天性心脏缺损。
研究人员也发现,miR-1-2会影响心脏负责调控心跳的电子传导。心脏节律的问题会导致猝死,而且需要使用心脏起搏器来改善。此外,缺少miR-1-2也使心脏细胞的分裂未受控制,导致成人心脏细胞无法分化,当心脏病发作时,心脏细胞会死亡而无法替补。
这项研究对于心脏发育及心脏病的成因有很大的贡献,研究人员除了更了解相关的发育机制之外,还可以针对这些缺陷造成的心脏问题对症下药,找出治疗心脏病患者的新疗法。
(资料来源 : Bio.com)
英文原文:
Gladstone Scientists Identify Critical Gene Factor in Heart Development
03/29/07 -- Researchers at the Gladstone Institute of Cardiovascular Disease (GICD) announced they have identified a critical genetic factor in the control of many aspects of heart form and function. As reported in the journal Cell, scientists in the lab of Deepak Srivastava, MD, have successfully deleted a genetic factor, called a microRNA, in animal models to understand the role it plays in cardiovascular differentiation and development.
MicroRNAS, or miRNAs, seem to act as rheostats or "dimmer switches" to fine-tune levels of important proteins in cells. To learn how microRNAs do this, the team led by Dr. Srivastava, deleted the gene responsible for one microRNA in mice and examined the effects of its loss on heart development and maintenance. "Knocking out" a gene is a favorite method for figuring out what a particular gene does in a cell by selectively removing it.
"Development of the heart requires very careful regulation of many factors, and that's one reason that microRNAs are so exciting to us," said Dr. Srivastava, GICD Director. "By knocking out the gene for one miRNA, we could determine exactly what it contributes to that complex process."
MicroRNAs exert their control by stopping protein production after the genes have directed them to be made. Previously, it was thought that all the control was at the level of the genes. Although only 20-22 nucleotides long, the microRNAs bind to the much longer messenger RNAs and prevent their blueprint for building a protein from being used. They typically prevent many messenger RNAs from making proteins and therefore can affect myriad events.
The Gladstone team looked at one particular microRNA, miR-1-2, that was active specifically in the heart. A closely related and redundant microRNA miR-1-1 could not fully compensate for loss of miR-1-2. The team found that loss of miR-1-2 affected many functions in the heart, including heart morphogenesis and control of the number of cells in the heart. For example, half of the mice developed holes in the pumping chambers of the heart, which is the most common human congenital heart defect.
They also found that miR-1-2 influences electrical conduction of the heart, which is what regulates the heart beat. Defects in the heart rhythm frequently cause sudden death in humans and are the reason for pacemakers and defibrillators.
Loss of miR-1-2 also caused a breakdown of the control of cell division in the heart cells. This is potentially a very important finding. Adult heart cells do not divide. When a heart attack occurs, heart cells die and cannot be replaced. Understanding how cell division works in the heart may lead to ways to turn it back on or to use stem cells to fix the damaged heart.
Finally, the team was able to see all of the genes that a specific microRNA affects. Each microRNA is known to control more than one gene. Dr. Srivastava's team used genomic studies to examine all of the genes that were turned on or off by the loss of miR-1-2. This information will help to determine the global picture of microRNA control.
"Our results show that even small changes in microRNA dosage can have large effects," said Yong Zhao, MD, PhD, postdoctoral fellow and lead author on the paper. "Although any therapies are a long way off, understanding the effects of miR-1-2 is very exciting," added Joshua Ransom, a graduate student who contributed equally to this work."
Source: Gladstone Institutes
参考文献:
Copyright © 2006 Cell Press. All rights reserved.
Cell, Vol 126, 1037-1048, 22 September 2006
Review
Making or Breaking the Heart: From Lineage Determination to Morphogenesis
Deepak Srivastava1,
1 Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA
Corresponding author
Deepak Srivastava
dsrivastava@gladstone.ucsf.edu
Summary
The cues governing cardiac cell-fate decisions, cardiac differentiation, and three-dimensional morphogenesis are rapidly being elucidated. Several themes are emerging that are relevant for childhood and adult heart disease and the growing field of stem cell biology. This review will consider our current understanding of cardiac cell-fate determination and cardiogenesis—largely derived from developmental studies in model organisms and human genetic approaches—and examine future implications for diagnosis, prevention, and treatment of heart disease in the young and old.