MicroRNA的發(fā)現(xiàn)使生物學(xué)許多領(lǐng)域都向前邁進(jìn)一大步,。研究人員發(fā)現(xiàn),，microRNA在心臟細(xì)胞的生長(zhǎng)及分化過程中，扮演著極其重要的平衡角色。
Gladstone心臟疾病研究所的(GICD)研究人員日前宣布，他們辨認(rèn)出一個(gè)與心臟型態(tài)及功能有關(guān)的重要遺傳因素,。根據(jù)這篇發(fā)表于Cell的研究報(bào)告，Deepak Srivastava等人成功地刪除了小鼠模型中,，一種稱為microRNA的遺傳因素,，以了解miRNA在心血管分化和發(fā)育過程中扮演的角色。
MicroRNAs (miRNAs)是一種大小約21—23個(gè)堿基的單鏈小分子RNA,，是由具有發(fā)夾結(jié)構(gòu)、約70-90個(gè)堿基大小的單鏈RNA前體,，經(jīng)過Dicer酶加工后生成,，不同于siRNA，但是和siRNA有密切的關(guān)連性,。
心臟的發(fā)育與許多因素有關(guān),，研究人員剔除了負(fù)責(zé)編碼miRNA的基因，以徹底了解miRNA對(duì)于心臟發(fā)育之復(fù)雜過程的貢獻(xiàn),。
研究人員調(diào)查一種名為miR-1-2的microRNA,，這個(gè)基因產(chǎn)物在心臟和肌肉組織中大量表現(xiàn)。另外一個(gè)與miR-1-2有關(guān)的microRNA是miR-1-1,，miR-1-1無法補(bǔ)償缺乏miR-1-2時(shí),，對(duì)于心臟發(fā)育造成的影響。
研究人員發(fā)現(xiàn),，當(dāng)小鼠失去了miR-1-2,，心臟功能受到極大的影響，包括心臟的的形態(tài)發(fā)生和心臟細(xì)胞數(shù)量的控制,。其中半數(shù)的小鼠發(fā)生的心室穿孔,，而心室穿孔是最常見的人類先天性心臟缺損。
研究人員也發(fā)現(xiàn),，miR-1-2會(huì)影響心臟負(fù)責(zé)調(diào)控心跳的電子傳導(dǎo),。心臟節(jié)律的問題會(huì)導(dǎo)致猝死，而且需要使用心臟起搏器來改善,。此外,，缺少miR-1-2也使心臟細(xì)胞的分裂未受控制，導(dǎo)致成人心臟細(xì)胞無法分化,，當(dāng)心臟病發(fā)作時(shí),，心臟細(xì)胞會(huì)死亡而無法替補(bǔ)。
這項(xiàng)研究對(duì)于心臟發(fā)育及心臟病的成因有很大的貢獻(xiàn),，研究人員除了更了解相關(guān)的發(fā)育機(jī)制之外,，還可以針對(duì)這些缺陷造成的心臟問題對(duì)癥下藥,，找出治療心臟病患者的新療法。
(資料來源 : 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
參考文獻(xiàn)：
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
[email protected]
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.
