let-7 miRNAs Can Act through Notch to Regulate Human Gliogenesis.
In this paper we showed that a family of small non-coding RNAs can regulate the developmental maturity of human pluripotent stem cell progeny in the neural lineage. As a result, we developed tools that allow for researchers to make certain types of brain cells much more quickly and easily.
It is clear that neural differentiation from human pluripotent stem cells generates cells that are developmentally immature. Here, we show that the let-7 plays a functional role in the developmental decision making of human neural progenitors, controlling whether these cells make neurons or glia. Through gain- and loss-of-function studies on both tissue and pluripotent derived cells, our data show that let-7 specifically regulates decision making in this context by regulation of a key chromatin-associated protein, HMGA2. Furthermore, we provide evidence that the let-7/HMGA2 circuit acts on HES5, a NOTCH effector and well-established node that regulates fate decisions in the nervous system. These data link the let-7 circuit to NOTCH signaling and suggest that this interaction serves to regulate human developmental progression.