The impressive neuronal diversity found within the nervous system emerges from a limited pool of neural progenitor cells that proceed through different gene expression programs to acquire distinct cell fates. Here, we review recent evidence indicating that microRNAs (miRNAs) are critically involved in conferring neural cell identities during neural induction, neuronal differentiation and subtype specification. Several studies have shown that miRNAs act in concert with other gene regulatory factors and genetic switches to regulate the spatial and temporal expression profiles of important cell fate determinants. So far, most studies addressing the role of miRNAs during neurogenesis were conducted using animal models. With the advent of human pluripotent stem cells and the possibility to differentiate these into neural stem cells, we now have the opportunity to study miRNAs in a human context. More insight into the impact of miRNA-based regulation during neural fate choice could in the end be exploited to develop new strategies for the generation of distinct human neuronal cell types.

MicroRNAs are key regulators of neural cell proliferation, differentiation and fate choice. Due to the limited access to human primary neural tissue, the role of microRNAs in human neuronal differentiation remains largely unknown. Here, we use a population of long-term self-renewing neuroepithelial-like stem cells (lt-NES cells) derived from human embryonic stem cells to study the expression and function of microRNAs at early stages of human neural stem cell differentiation and neuronal lineage decision. Based on microRNA expression profiling followed by gain- and loss-of-function analyses in lt-NES cells and their neuronal progeny, we demonstrate that miR-153, miR-324-5p/3p and miR-181a/a* contribute to the shift of lt-NES cells from self-renewal to neuronal differentiation. We further show that miR-125b and miR-181a specifically promote the generation of neurons of dopaminergic fate, whereas miR-181a* inhibits the development of this neurotransmitter subtype. Our data demonstrate that time-controlled modulation of specific microRNA activities not only regulates human neural stem cell self-renewal and differentiation but also contributes to the development of defined neuronal subtypes.