Trends in Biochemical Sciences
ReviewA developmental view of microRNA function
Introduction
In metazoans, early embryonic patterning and organ morphogenesis involve coordinated differentiation, migration, proliferation and programmed cell death. These complex cellular and developmental processes depend on precise spatiotemporal regulation of mRNA and protein levels of key regulatory factors. The dose-sensitivity of proteins involved in morphogenesis is highlighted by the numerous human diseases caused by heterozygous mutations that result in haploinsufficiency. Protein levels can be controlled at multiple stages, including mRNA transcription and translation, and protein stability and degradation.
Animal species use evolutionarily conserved mechanisms, ranging from signaling events to chromatin remodeling and transcriptional regulation, to execute developmental programs. In recent years, evidence has accumulated that small non-coding RNAs are also used in a conserved manner to regulate key developmental events. At least four classes of regulatory small non-coding RNAs have been described, including microRNAs (miRNAs), short interfering RNAs (siRNA), repeat-associated small interfering RNAs (rasiRNAs) and piwi-interacting RNAs (piRNAs) 1, 2. Among these small RNAs, miRNAs are the most phylogenetically conserved and function post-transcriptionally to regulate many physiologic processes, including embryonic development 3, 4, 5, 6, 7.
The first known animal miRNA, lin-4, was discovered in a screen of Caenorhabditis elegans heterochronic genes, which distinguish one larval development stage from another. Analysis of the heterochronic pathway then led to the identification of the first miRNA target, lin-14 3, 4. The discovery that another miRNA, let-7, is conserved from worms to mammals 5, 8 resulted in the realization that miRNAs represent a widely used mechanism to regulate transfer of genetic information in almost all species. Over the past few years, >400 miRNAs have been identified, and there are probably many more still undiscovered 9, 10, 11, 12, 13, 14. Systematic analysis of the spatial expression of miRNAs has shown that many miRNAs are expressed in a tissue-specific manner 15, 16. Because each miRNA targets a large number of mRNAs for translational inhibition or degradation, it is likely that much of the transcriptome is regulated by miRNAs. Given the likely role of miRNAs in ‘fine-tuning’ protein dosage, they might represent an efficient system by which a cell can rapidly control threshold-dependent cellular events.
Adoption of cell lineages during embryonic development and subsequent morphogenetic events are mainly achieved by rapid and regional regulation of morphogen gradients that subsequently titrate transcriptional events during discrete windows of time. As a result, miRNAs might have a fundamental role in many, if not most, crucial embryonic decisions. During the past few years, several examples of miRNA regulation of developmental events have emerged that support such a notion. Progress in understanding the transcriptional regulation of miRNAs and identification of their targets provides an opportunity to dissect the complex networks involved in regulating protein dosage during cell-fate decisions and further embryogenesis. Here, we review recent conceptual advances in the transcriptional- and post-transcriptional regulation of miRNAs, their target recognition and the mechanisms by which miRNAs might regulate developmental events. Although the paradigms described here are relevant to miRNA biogenesis and function in other settings, owing to space constraints, we cannot review all aspects of miRNA biology but refer readers to several outstanding recent reviews 17, 18, 19, 20, 21, 22, 23.
Section snippets
Overview of the generation and function of miRNAs
A brief review regarding general features of miRNA biogenesis and function is provided here, which will be relevant to later discussions of developmental-specific miRNA biology. Numerous reviews provide more details regarding miRNA biogenesis (see, for example, Refs 18, 23, 24, 25, 26).
Target recognition: miRNA-seed pairing and RNA accessibility
The biology of miRNA function will be dictated by the mRNA transcripts targeted by specific miRNAs. However, it has been difficult to predict miRNA targets by nucleotide-sequence matching because of limited sequence complementarity even in the setting of efficient translational inhibition. There is good evidence that a high degree of complementarity with the 5′ end of the miRNA, particularly nucleotides 2–7, is important in target-mRNA recognition 27, 28, 29. However, even among these six
miRNA functions: a developmental view
The dynamic nature of protein expression during cell-lineage decisions and subsequent morphogenetic events would be consistent with extensive regulation by miRNAs. In recent years, examples of tissue-specific roles of miRNAs during embryonic development have emerged and are reviewed here. Specifically, we focus on miRNA regulation of cardiac and skeletal muscle, neurons and hematopoietic lineages because accumulating evidence indicates pivotal functions for miRNAs in development of these cell
Modes of miRNA-mediated regulation
Many paradigms have emerged over the past decade that govern the precise and coordinated interpretation of genetic information during embryonic development. As a recently recognized part of that regulation, miRNA-mediated events seem to ensure the preciseness and fidelity of dynamic and spatially restricted gene expression during development. Some aspects of miRNA-mediated regulatory circuits that might control developmental events are considered here.
Concluding remarks
The past several years have witnessed tremendous progress in our understanding of miRNAs. Many have important roles in a broad range of developmental processes, but the number of miRNAs and their roles are still emerging. However, it is becoming clear that miRNAs are integrally involved in the complex regulatory networks that govern the developmental, homeostatic and physiological processes of most organisms. Because this field is still in its infancy, several important questions remain. The
Acknowledgements
We thank B. Taylor for assistance with manuscript preparation, members of the Srivastava laboratory for discussions, insight and reviewing of the manuscript, and S. Ordway and G. Howard for editorial assistance. Y.Z. is a California Institute of Regenerative Medicine (CIRM) Post-Doctoral Scholar; D.S. is supported by grants from the NHLBI/NIH and the March of Dimes Birth Defects Foundation; D.S. is an Established Investigator of the American Heart Association.
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