microRNAs as Developmental Regulators

Abstract

The field of miRNA biology is relatively young, but its impact on our understanding of the regulation of a wide array of cell functions is far-reaching. The importance of miRNAs in development has become nearly ubiquitous, with miRNAs contributing to development of most cells and organs. Although miRNAs are clearly interwoven into known regulatory networks that control cell development, the specific modalities by which they intersect are often quite distinct and cleverly achieved. The frequently emerging theme of feed-back and feed-forward loops to either counterbalance or reinforce the gene programs that they influence is a common thread. Many of these examples of miRNAs as developmental regulators are presently found in organs with different miRNAs and targets, whereas novel, unexpected themes emerge in the context of mouse development as we learn more about this rapidly developing area of biology.

Figure 1.

miRNA biogenesis. Schematic representation of miRNA biogenesis and function. Transcription of miRNA genes is typically mediated by RNA (Pol II). The initial miRNA-containing transcript, termed primary miRNAs (pri-miRNAs), can range from a few hundred nucleotides to several kilobases long. Inside the nucleus, the pri-miRNA has a characteristic stem-loop structure that can be recognized and cleaved by the ribonuclease III (RNase III) endonuclease Drosha along with its partner DGCR8 (DiGeorge syndrome critical region 8 gene; also known as Pasha). The cleavage product, a ∼70-nucleotide stem-loop pre-miRNA, is exported from the nucleus by exportin 5. In the cytoplasm, another RNase III enzyme, Dicer, further cleaves the pre-miRNA into a double-stranded mature miRNA (∼21 nucleotides) that is incorporated into the RNA-induced silencing complex (RISC), allowing preferential strand separation of the mature miRNA to repress mRNA translation or destabilize mRNA transcripts through cleavage or deadenylation. SRF, serum response factor; TF, transcription factor. (Adapted from Zhao and Srivastava 2007.)

Figure 2.

Common mechanisms of developmental regulation by miRNAs. (A) miRNAs modulate proliferation of differentiating cells by targeting either positive or negative cell-cycle regulators. (B) miRNAs act in regulatory loops to ensure complete commitment to specific cell lineages during development. (C) Multiple lineage-promoting miRNAs can converge on a single pathway to cooperatively regulate cell fate. (D) miRNAs act in regulatory loops with self-renewal genes to maintain the balance between progenitor cells and their differentiated progeny. (Adapted from Ivey and Srivastava 2010.)

Figure 3.

Summary of miR-1 and miR-133 genomic organization, regulation, and expression during cardiogenesis. (A) Chromosome locations of miR-1 and miR-133a orthologs. The miR-1-2/miR-133a-1 cluster is intragenic, and the miR-1-1/miR-133a-2 cluster is intergenic. miR-1/133a clusters are transcribed as bicistronic transcripts. (B) Cardiac- (red) and muscle- (green) specific expression of miR-1 and miR-133 clusters is regulated by SRF and myogenic transcription factors Mef2 and MyoD. Targets of miR-1 and miR-133 that regulate cardiac or skeletal muscle are shown. (C) LacZ directed by an upstream enhancer of the miR-1-2/miR-133a-2 cluster and miR-1-1/miR-133a-1 cluster, respectively, shows expression in the heart (ht) and somites (arrowhead) at mouse embryonic day 11.5. (From Cordes and Srivastava 2009; adapted, with permission.)