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Micromanaging Development
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MicroRNAs are a key part of the fine regulation of development in many organ systems
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The discovery of microRNAs (miRNAs) opened up an exciting new level of genetic control. These small RNAs of 20?25?nucleotides do not encode a protein, but control protein expression by binding to messenger RNAs (mRNAs) and regulating their translation or stability. In doing so, they are part of the intricate control processes that build our tissues and organs. In fact, the 2008 Lasker Award went to the discoverers of miRNAs.
?Biology is filled with surprises. Just when we believe we understand how things work, something new is found,? said Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease. ?MicroRNAs are one of those, and understanding them will help us to understand many aspects of normal and abnormal development.?
miRNAs seem to act as rheostats or ?dimmer switches? to fine-tune levels of important proteins in cells. More than 650?human miRNAs have been described, and each is predicted to regulate tens if not hundreds of proteins that control the biological properties of the cells.
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Fen-Biao Gao (L) and Deepak Srivastava
Future Directions
miRNAs are an exciting new layer of genetic regulation. Over 650 miRNAs are known, but few have been characterized. Every study furthers our understanding of how these mysterious small molecules control translation, development, and other cellular activities. As their functions become better known, we will have a much better understanding of normal and disease processes, and we will have many new therapeutic targets.
?miRNAs offer biomedical scientists a new window on development,? said Dr. Srivastava. ?One can only wonder what we will be able to do with the knowledge we gain from the study of their activities.?
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But how do miRNAs actually work and can they be used to treat diseases? Gladstone scientists have been at the forefront of answering these questions. The first knockout of a mouse miRNA was accomplished in Dr. Srivastava?s laboratory (Zhao et al., Cell 2007), and the first characterization of a miRNA in a neurological system was made by the laboratory of Fen-Biao Gao (Li et al., Genes Dev. 2006). In addition, Dr. Srivastava has been funded by the National Heart, Lung, and Blood Institute to knock out all the miRNAs that are enriched in the heart as a resource to the scientific community.
In a recent series of studies, they have made significant findings about how miRNAs contribute to the development of the heart, vasculature, and the nervous system. In addition, they have explored how miRNAs find and bind to their specific target mRNAs to control the translation of proteins.
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Papers Cited
Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DYR, Srivastava D (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15:272?284.
Ivey KN, Muth A, Arnold J, King FW, Yeh RF, Fish JE, Hsiao EC, Schwartz RJ, Conklin BR, Bernstein HS, Srivastava D (2008) MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2:219?229.
Li Y, Wang F, Lee J-A, Gao F-B (2006) MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila. Genes Dev. 20:2769?2805.
Morton SU, Scherz PJ, Cordes KR, Ivey KN, Stainier DYR, Srivastava D (2008) microRNA-138 modulates cardiac patterning during embryonic development. Proc. Natl. Acad. Sci. USA 105:17830?17835.
Xu XL, Li Y, Wang F, Gao FB (2008) The steady-state level of the nervous-system-specific microRNA-124a is regulated by dFMR1 in Drosophila. J. Neurosci. 28:11883?11889.
Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303?317.
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