Cell fate: Small RNAs make big decisions

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Micro RNAs may have a crucial role in the signaling processes that govern vertebrate cell fate decisions.

Micro RNA (miRNA) regulates gene expression during invertebrate and plant development, however, this has not yet been shown in vertebrate ontogenesis. Among the developmentally important invertebrate miRNAs, miR-214 is known to control larval stage transition in C. elegans. Flynt et al. now show in Nature Genetics that the Zebrafish miR-214 paralogue influences Hedgehog signaling and is required for the specification of muscle cell fate during somitogenesis.

The skeleton and muscles develop from transient embryonic tissues called somites. Injection of miR-214 antisense morpholino oligonucleotides (214^MO) into Zebrafish embryos caused somites to become aberrantly shaped, as well as drastically reducing the number of muscle pioneer cells. As muscle pioneer cell development requires high levels of Hedgehog signaling, this result suggests a disruption in this pathway. Administration of synthetic Hedgehog rescued the morpholino phenotype, demonstrating a role for miR-214 in Hedgehog signaling. Furthermore, miR-214 misexpression lead to the perturbation of Hedgehog-dependent markers in the ventral neural tube.

Suppressor of fused (su(fu)) — a negative regulator of Hedgehog signaling — is crucial for the correct specification of muscle cells during somitogenesis. Su(fu) is a predicted target of miR-214 and its expression was significantly lowered after miR-214 injection into embryos. Thus, the reduced number of pioneer cells correlates with the upregulation of su(fu) due to the loss of miR-214 expression. Ablation of Su(fu) mRNA expression in 214^MO-injected embryos resulted in the suppression of muscle pioneer deficiency. This observation suggests that miR-214

Su(fu), in turn, binds to the Gli family of transcription factors. Su(fu) binding blocks Gli proteins, among which are activators as well as repressors. Gli activators are present in the group of adaxial presomitic cells that pioneer cells arise from, whereas Gli repressors are active in the lateral presomites that develop into fast muscle cells. Thus, the increased presence of su(fu) caused by miR-214 inhibition leads to a reduction in Gli activators and repressors in adaxial and lateral presomites, respectively. This explains the stunning finding that expression of patched1, a Hedgehog ligand receptor whose transcription is activated by Hedgehog, is downregulated in adaxial but upregulated in lateral cells. miR-214 inhibition can therefore lead to opposite alterations of Hedgehog signaling.

Together, the results of Flynt et al. indicate that miRNAs may have a crucial role in the signaling processes that govern vertebrate cell fate decisions.

Mirko von Elstermann
Functional Glycomics Gateway

References

Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG. Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate. Nature Genetics 39, 259-263 (2007) | Article | PubMed |