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Keywords:

  • BMP ;
  • hsa-miR-135b;
  • human embryonic stem cells;
  • microRNA;
  • neuroectoderm;
  • PAX6;
  • TGF-β;
  • transcription factor

Abstract

Several transcription factors (TFs) have been implicated in neuroectoderm (NE) development, and recently, the TF PAX6 was shown to be critical for human NE specification. However, microRNA networks regulating human NE development have been poorly documented. We hypothesized that microRNAs activated by PAX6 should promote NE development. Using a genomics approach, we identified PAX6 binding sites and active enhancers genome-wide in an in vitro model of human NE development that was based on neural differentiation of human embryonic stem cells (hESC). PAX6 binding to active enhancers was found in the proximity of several microRNAs, including hsa-miR-135b. MiR-135b was activated during NE development, and ectopic expression of miR-135b in hESC promoted differentiation toward NE. MiR-135b promotes neural conversion by targeting components of the TGF-β and BMP signaling pathways, thereby inhibiting differentiation into alternate developmental lineages. Our results demonstrate a novel TF-miRNA module that is activated during human neuroectoderm development and promotes the irreversible fate specification of human pluripotent cells toward the neural lineage.

Synopsis

Thumbnail image of graphical abstract

A genome-wide association study on the neural inducer Pax6 identifies miR-135b as a novel Pax6 target that promotes neuroectoderm (NE) induction by antagonizing BMP and Activin/Nodal signals.

  • Genome-wide study to identify downstream targets of the master transcriptional regulator Pax6 in human NE;
  • Reports direct Pax6 localization to promoters of several TFs known to govern neural differentiation;
  • Reveals Pax6 regulation of microRNAs involved in neural specification;
  • Identifies Pax6 regulation of miR-135b to inhibit TGF-β and BMP signals and thus facilitate NE specification.