The miR-430/427/302 Family Controls Mesendodermal Fate Specification via Species-Specific Target Selection

Abstract

The role of microRNAs in embryonic cell fate specification is largely unknown. In vertebrates, the miR-430/427/302 family shows a unique expression signature and is exclusively expressed during early embryogenesis. Here, we comparatively address the embryonic function of miR-302 in human embryonic stem cells (hESCs) and its ortholog miR-427 in Xenopus laevis. Interestingly, we found that this miRNA family displays species-specific target selection among ligands of the Nodal pathway, with a striking conservation of the inhibitors, Lefties, but differential targeting of the activators, Nodals. The Nodal pathway plays a crucial role in germ layer specification. Accordingly, by gain and loss of function experiments in hESCs, we show that miR-302 promotes the mesendodermal lineage at the expense of neuroectoderm formation. Similarly, depletion of miR-427 in Xenopus embryos hinders the organizer formation and leads to severe dorsal mesodermal patterning defects. These findings suggest a crucial role for the miR-430/427/302 family in vertebrate embryogenesis by controlling germ layer specification.

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network

“…15,[22][23][24][25][26][27] Consistent with our results, a previous report showed the importance of the miR-302-367 in cell differentiation by describing its role in the promotion of mesendodermal fate specification. 28 On the other hand, other reports described the miR-302-367 cluster as a stemness determinant in human embryonic stem cells (ESC) 29 and in inducible pluripotent stem cells (IPS) derived from human skin cancer cells. 30 In this context, the miR-302-367 promoter was transcriptionally regulated by the stemness transcription factors Oct4, Sox2, and Nanog; therefore, its expression in the ESC compartment and during early stages of mouse development was restricted.…”

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

“…The miR-302/-367 cluster also was highly enriched. This cluster reprograms somatic cells to induced pluripotent stem cells (iPSCs), whereas miR-302 promotes mesendoderm at the expense of neuroectoderm in human ESCs (26,27). The high enrichment of these clusters attests to successful capturing of important regulatory miRNAs.…”

MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo

“…18 A role for miRNAs in conferring robustness to the Nodal signaling pathway during early embryo development has been shown in zebrafish and xenopus embryos. 12,19,20 In zebrafish the miR-430 family of miRNAs modulates expression of both the Nodal homologue Squint and the nodal antagonist Lefty, thus helping to maintain the agonist/ antagonist balance. As a result, deletion of Dicer in zebrafish results in overexpression of both Squint and Lefty.…”

“…However in this case miR-427 appears to have a stronger effect on antagonist than agonist inhibition, as inhibiting expression of this miRNA results in a failure to differentiate mesoderm, a result also seen on either Lefty overexpression or Nodal signaling inhibition. 20 In mouse Nodal is expressed in the epiblast from the blastocyst stage and requires processing in the trophoblast by the convertases Spc1 and Spc4 to become fully active. 21,22 Its diffusible nature allows it to play important roles in the patterning and development of all three tissue lineages.…”