小RNA在什么地方？

Nature 425, 244 - 245 (18 September 2003); doi:10.1038/425244a

Molecular biology: MicroRNA is here to stay

PHILIP N. BENFEY

Philip N. Benfey is in the Department of Biology, Box 91000, Duke University, Durham, North Carolina 27708, USA.
e-mail: philip.benfey@duke.edu

A form of gene regulation that uses small RNA molecules to bind to longer RNAs was first described over a decade ago, but was thought to be of little significance in controlling cellular processes. No longer.

The first glimpse of the wave was more than a decade ago, when a strange form of gene regulation was described that involved the binding of one RNA molecule to another1. Then last year, with reports that there are hundreds of small RNAs in the genome2-5, it came into view. There was the possibility that a whole layer of gene regulation involving very small RNA molecules called microRNAs had been overlooked for 40 years. But still there were doubts as to the importance of microRNAs — the wave might yet turn out to be scarcely a ripple, let alone a tsunami. With the description by Palatnik et al. of the role of microRNAs in controlling plant development (page 257 of this issue6), and other new publications reporting important functions in animals7-9, the wave looks very real — and big.

In the beginning there was the view that DNA makes RNA makes protein, and life was simple and good. Other functions for RNA were discovered. But they were mostly structural, such as being a part of the ribosome, the cellular site of protein manufacture. Then in 1993, while studying mutations that changed the timing of developmental events in the worm Caenorhabditis elegans, Victor Ambros made a startling discovery1. A mutation that caused an increase in the translation of RNA to protein was found to be in a second, very small RNA molecule. The small RNA was shown to bind through base pairing to one end of an RNA that controlled the worm's ability to develop properly. The binding of the small RNA resulted in a block to translation of the messenger RNA. Seven years later, a second case of a small RNA used to regulate the translation of a messenger RNA was reported10. However, the small RNA was again found in worms and was controlling a similar developmental process. It was beginning to look as if this was just another baroque facet of evolution — a form of regulation that was highly specialized for one organism and one function.

What rescued microRNAs from neglect was genome sequencing. Several groups started to look for sequences within the genome that were transcribed into RNA but the RNAs were not used to make proteins. They combined bioinformatics searches with sophisticated procedures that allowed them to isolate only small RNAs. What they found was that in organisms ranging from plants to man there were hundreds of small RNAs (18–25 nucleotides) that were actively transcribed and highly conserved between related species2, 4, 5.

The next task was to determine what these microRNAs were doing. Last year, two groups published the dramatic findings that many of the apparent targets of plant microRNAs are transcription factors implicated in the control of developmental processes2, 4. Transcription factors are proteins that control gene activity. So the findings led to speculation that a primary role for microRNAs in plants is to regulate gene expression after a cell division event that leads to the formation of two different cell types. But to identify putative targets through bioinformatics is one thing. To prove that microRNAs are really regulating a developmental process is quite another.

Palatnik et al.6 have done just that, although it was not the original intent of their project. They were screening a collection of mutants of the plant Arabidopsis, made by randomly inserting a piece of DNA into the genome that increases transcription of neighbouring genes. They found several mutations that caused leaves to curl rather than lie flat. When they sequenced the region of the genome near the inserted DNA they discovered what appeared to be a gene encoding a microRNA named JAW. To identify possible targets of the microRNA, they used microarrays to compare the global expression profile of the jaw mutants with that of wild-type plants. Among the RNAs with the greatest differences were four members of the TCP class of transcription factors, which had been shown to control leaf curvature in snapdragon. Alignment of the JAW microRNA with the TCP RNAs showed near perfect complementarity (Fig. 1).

Figure 1 MicroRNAs in action. Full legend

High resolution image and legend (36k)

A series of elegant experiments showed that TCP gene function was indeed controlled by the JAW microRNA. The TCP sequence was modified so that the JAW microRNA could no longer bind while the protein made from the TCP RNA was not affected (Fig. 1). Introduction of this mutant form of the gene into wild-type plants resulted in severe developmental defects. That is, the microRNA could not carry out its job, which was evidently to control the availability of TCP protein.

Further evidence that the critical control point was exercised by microRNAs came from overexpressing a normal TCP RNA. For many transcription factors, overexpression of their RNA is like forcing too much electricity through a circuit. But overexpression of the TCP RNA caused no obvious defects. The same construct introduced into the jaw mutant was able to partially rescue the leaf-curling defect. The likely explanation is that in the jaw mutant, the inserted DNA causes too much JAW microRNA to be produced and it is no longer restricted to certain tissues. Making more of the target RNA sops up the excess JAW microRNA.

The paper by Palatnik et al.6 provides one of the most compelling cases that the newly discovered microRNAs have an important role in controlling development. Other recently published results highlight the involvement of microRNAs in regulating processes ranging from cell proliferation and programmed cell death in flies7 to neuronal differentiation in humans8. Among the many unanswered questions that surround microRNA function a central one is, what controls microRNA expression? Is there still another level of regulation that has been overlooked — another wave just beyond the horizon?

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