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Review
.2015 Jan;359(1):47-64.
doi: 10.1007/s00441-014-1981-y. Epub 2014 Aug 30.

The role of microRNAs in human neural stem cells, neuronal differentiation and subtype specification

Affiliations
Review

The role of microRNAs in human neural stem cells, neuronal differentiation and subtype specification

Laura Stappert et al. Cell Tissue Res.2015 Jan.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Schematic representation of miRNA-target interactions regulating neural lineage entry of hPS cells. (a) Overview of the miRNAs contributing to neural induction by influencing the activity of anti-neural BMP/TGFβ signaling (b) or by directly regulating the expression of pluripotency- and neural fate-associated transcription factors (c; miRNAs labeled inred have an inhibitory and miRNAs ingreen a promoting effect on neural induction. (b) Both miR-302 and miR-371 potentiate BMP signaling via targeting BMP inhibitors, thus creating a barrier for neural induction. Likewise, miR-200 promotes BMP signaling as part of a double-negative feed-back loop with the BMP repressor ZEB. In contrast, miR-125b and miR-135b interfere with BMP/TGFβ signaling by targeting SMAD4 and other important components of the BMP/TGFβ signaling cascade leading to an enhanced neural lineage entry. (c) In addition to its impact on BMP signaling, miR-302 also acts in concert with OCT4 to ensure repression of pro-neural NR2F2. Reciprocally, NR2F2 represses OCT4 expression, forming a double-negative feed-back loop. OCT4 directly represses miR-145 expression and indirectly inhibits let-7 maturation via induction of Lin28 expression. In turn, both miR-145 and let-7 repress the expression of pluripotency factors and promote differentiation. In contrast, miR-96 interferes with neural induction by targeting the neural lineage determinant PAX6. PAX6, in turn, activates other neuronal transcription factors and miR-135
Fig. 2
Fig. 2
MiR-124 and miR-9/9* engage in complex regulatory circuits activating a neuronal gene expression program. Expression of miR-124 and miR-9/9* is controlled by the neurogenic repressor REST and its co-factors SCP1 and CoREST. In addition, miR-9/9* is repressed by TLX and the Notch effector HES1. During neuronal differentiation, miR-124 and miR-9/9* are up-regulated and reinforce their own expression by targeting their negative regulators. For instance, miR-9 forms auto-regulatory loops with HES1 and the let-7 target TLX. Both miR-124 and miR-9/9* repress the expression of additional components of the Notch pathway (PW). Furthermore, forced expression of miR-124 and miR-9/9* induces a switch of epigenetic regulators. MiR-124 and miR-9* favor the switch from BAF53a to BAF53b to be included in the BAF chromatin remodeling complex leading to the induction of dendritic outgrowth. In addition, miR-124 targets the mRNA splicing regulator PTBP1 allowing the expression of the neuron-enriched homolog PTBP2, which induces a neuron-specific pre-mRNA splicing pattern. Down-regulation of PTBP1 also leads to the abolishment of its inhibitory impact on the interaction of miR-124 with REST co-factor SCP1
Fig. 3
Fig. 3
Lt-NES cells can be used to study miRNA functions associated with human neuronal differentiation. (a-d) Self-renewing lt-NES cell form small neural rosettes with characteristic ZO1 expression in the lumen (b,d). They express the neural stem cell markers Nestin (b), SOX2 (c) and PLZF (d). (e) When induced to enter differentiation by growth factor withdrawal, lt-NES cells give rise to β-III tubulin-positive neurons as shown here after 7 days of differentiation. (f) The rate of neuronal differentiation can be further increased by lentivirus-mediated overexpression of neuronal fate-associated miRNAs such as miR-181a/a*.Ctr lt-NES cell cultures transduced with a control lentiviral construct coding for a scrambled miRNA.DAPI labels nuclei, allscale bars 50 μm. The pictures in (c,d) were kindly provided by Johannes Jungverdorben
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