Abstract Robustness is a fundamental property of biological systems. Here, we discuss the roles that microRNAs play in providing canalization to animal development, citing recent theoretical and experimental advances. MicroRNAs repress protein expression, and they do this in ways that create thresholds in expression and provide adaptation to regulatory networks. Numerous examples have now been described where the developmental impact of environmental variation is suppressed by individual microRNAs.

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David A. Abstract During development, angiogenesis occurs as a controlled series of events leading to neovascularization that supports changing tissue requirements. Several pro- and antiangiogenic factors orchestrate a complex, dynamic process to allow initial sprouting and invasion, subsequent pruning and remodeling, and finally maturation and survival of blood vessels.

In the last decade, a new class of small RNA molecules termed micro-RNAs miRs have emerged as key regulators of several cellular processes including angiogenesis. Micro-RNAs such as miR, miR, miR, miR, and miRa have been shown to play pro- and antiangiogenic roles in the vasculature of both endothelial cells and perivascular cells. However, in pathological situations such as cancer or inflammation, the same angiogenic signaling pathways and miRs are dysregulated and exploited, typically resulting in poorly organized vessels with leaky and tortuous properties.

This article is a brief overview of specific miRs that have been reported to play a role in the vasculature. The authors explore emerging principles that suggest miRs insulate cellular processes from external perturbations and provide robustness to biological systems in the context of angiogenesis.

The quiescent endothelium resumes an active proliferation program that results in growth of new blood vessels governed by a complex milieu of growth factors and signaling networks to generate new blood vessels in a process broadly termed angiogenesis.

Some of these proliferation programs and signaling networks are fundamental processes that shape the development of vasculature in the embryo and are reactivated and rewired during pathological neovascularization.

In the past decade or so, it has become increasingly clear that small noncoding RNAs, particularly micro-RNAs miRs , in the genome rapidly respond to stimuli and facilitate physiological processes including angiogenesis. This review will focus on a few examples from endothelial biology in which the role of miRs seems to provide a critical threshold to facilitate or inhibit angiogenic responses. A Brief Primer on miRs miRs are small to nucleotide sequences most often found in the intronic or intergenic regions.

This triggers the recruitment of a host of other proteins that can modify RNA molecules, and the target mRNA is deadenylated, decapped, and degraded by exonucleases. In general, it is thought that miR-mediated repression of translation contributes to a decrease in protein output that often correlates with the decrease in mRNA levels of the targets.

These mice had severe vascular deformation in the embryo and yolk sac and died at E Subsequently, selective ablation of Dicer in mouse endothelium also led to significant defects in postnatal angiogenesis in response to a variety of stimuli such as growth factors, ischemia, and wound healing.

Specific miRs Implicated in Angiogenesis Several excellent reviews have comprehensively addressed the different miRs that play a role in angiogenesis and cardiovascular development. The same group followed up with loss-of-function studies in miR knockout mice, showing that miR-1 was critical for cardiogenesis, cardiac conduction, and cell cycle.

Also, these mice have a decrease in blood pressure and enhanced development of atherosclerotic lesions. Using gain and loss-of-function studies, we showed that miR affected endothelial proliferation, tube formation in vitro, and both developmental and pathological angiogenesis in vivo.

We were able to demonstrate that there is a reciprocal relati onship between miR and pRasGAP during vascular hyperproliferation, including hemangiomas and tumor angiogenesis. Lagos et al 30 reported that miR is upregulated with similar kinetics and plays a key role in lymphatic endothelial cells during viral infections.

Our observations highlight that miR not only is among the early response genes in endothelial activation but also is a critical regulator of the downstream events that control endothelial proliferation, tube formation, and angiogenesis in vivo.


Canalization of development by microRNAs

PLoS Biol 8 6 : e This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: No specific funding was received for this work. Competing interests: The author has declared that no competing interests exist. It does not happen often that an entirely novel gene regulatory mechanism is revealed.


MicroRNAs and their roles in developmental canalization


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