Developmental biology

Tiny brakes for a growing heart

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The discovery of microRNAs has revolutionized many areas of biology. The latest news is that these RNAs seem to regulate the crucial balance between growth and specialization of cardiac cells.

MicroRNAs (miRNAs for short) are tiny RNA molecules that downregulate protein production, either by inhibiting the translation of protein from messenger RNA or by promoting the degradation of mRNA1,2. In plants, miRNAs have major influences on embryonic development, primarily by slowing down the production of proteins that regulate gene expression. In vertebrates, the functions of miRNAs are less apparent, but — intriguingly — some miRNAs are expressed in specific tissues3,4,5,6. How these miRNAs are restricted to, say, the heart or the brain is not known, nor is it clear what they are doing there. In this issue, striking results from Zhao et al.7 (page 214) implicate miRNAs in controlling heart development in mouse embryos. The work places miRNAs both upstream and downstream of known cardiac gene-regulation cascades, and provides an exciting basis for understanding the regulation of organ formation.

Zhao et al.7 characterized two related miRNA genes, miR-1-1 and miR-1-2 (collectively known as miR-1), the products of which are enriched in heart and muscle3,4. Locating miRNAs in embryonic structures is technically challenging. To achieve this, Zhao et al. used a ‘reporter’ that produces a blue stain, which means it can easily be tracked. To mimic the expression pattern of the miR-1 gene, they spliced the gene encoding the reporter to the stretch of DNA in front of the miR-1 gene — the equivalent region of a protein-coding gene would normally carry regulatory information.

Zhao et al. found that the reporter was expressed in the heart and muscle of embryonic mice, and that the expression was controlled by several key heart and muscle transcription factors (proteins that regulate gene expression): serum response factor (SRF), Mef2 and MyoD. These results show that miRNAs are regulated just like ordinary genes, and therefore can potentially respond to the same developmental cues as other genes. As with miRNAs in zebrafish8, mouse miR-1 switches on rather late in heart development, implying that it acts after some of the main developmental steps have taken place.

So what does miR-1 do in the heart? Some clues about the function of miRNAs in embryo development come from experiments that disrupt the formation of all miRNAs by inactivating Dicer, an enzyme essential for miRNA production. In zebrafish, inactivation of Dicer leads to defects in the formation of the brain and heart8. However, it is not clear which miRNAs have developmental roles, or which genes they target. Using mice that are genetically modified to express miR-1 throughout the heart from a very early stage in heart development, Zhao et al. show that precocious expression of miR-1 leads to defects in heart formation because of decreased cell division (hence fewer heart cells). So, miR-1 may help regulate the balance between cardiac differentiation (specialization) and cell division, by slowing down proliferation at the right time.

But what are the targets of miR-1 in heart development? A major appeal of Zhao et al.'s work7 is that the authors claim to have devised a better way of identifying ‘real’ miRNA targets. Several approaches have been published, each claiming to be more efficient and specific than the previous one, so what makes Zhao et al.'s approach stand out? Significantly, their predictions are borne out by real data from an experimental system. However, they seem not to have found all the miR-1 targets, so although their predictions are correct, the criteria used by Zhao et al. may have been too restrictive to pick out all the targets. Time will tell if their method is indeed superior.

One of the principal miR-1 targets they identify is Hand2, a cardiac transcription factor (Fig. 1). Hand2 is expressed early in heart development and is involved in regulating its growth9. However, Hand2 is expressed continuously throughout heart development, and it is not known whether it continues to perform the same functions late in development as it did during the earliest stages. A simple interpretation of these observations would be that after Hand2 has performed its crucial tasks, miR-1 halts the production of Hand2 protein from the Hand2 mRNA, thus slowing down the growth of the heart (Fig. 1b, c).

Figure 1: Heart development and miR-1.
figure1

a, The timing of miR-1 action during heart development. In the early stages of heart development, the gene encoding miR-1 is off, and Hand2 is produced. At later stages, miR-1 switches on to reduce production of Hand2 protein, thereby slowing the growth of the heart. b, c, Proposed mechanism of miR-1 function. b, The expression of the Hand2 gene produces an mRNA that is normally translated into Hand2 protein. c, After Hand2 has completed most of its developmental tasks, miR-1 halts the translation of the protein.

Of course one might ask, why not just turn off the Hand2 gene at the right time? Because miRNAs have several targets, it may be more efficient to slow the production of several proteins by simply turning on one miRNA gene. Therefore the role of developmentally expressed miRNAs may be to titrate out regulatory molecules, such as transcription factors, to finely regulate organ growth and differentiation.

Zhao et al.'s findings open up a whole new dimension to the regulation of organ formation, by adding an miRNA-dependent regulatory step to the complex role of transcription factors. But many questions remain. For example, how are miR-1 genes turned on so relatively late in development? Are there factors that delay the activation of the miR-1 genes, and if so what are they? Moreover, it is unlikely that Hand2 is the sole target of miR-1 in the heart, so what else needs to be halted by miR-1 for normal heart development to proceed? The genetic deletion of miR-1 will no doubt help to answer these questions. Finally, because aberrant cardiac patterning during embryonic development can lead to congenital heart defects in humans9,10, are miRNAs also involved in these disease processes?

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Bruneau, B. Tiny brakes for a growing heart. Nature 436, 181–182 (2005) doi:10.1038/436181a

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