MicroRNA-Based Promotion of Human Neuronal Differentiation and Subtype Specification

Abstract

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.

Inhibition of miR-181a promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s disease

“…This hypothesis would also be consistent with the finding that TGF- and BMP ligands have potent neuroprotective effects in mDA neurons in vivo [26,27]. Finally, miR-181a was recently shown to induce neuronal differentiation and a DA phenotype in human long-term self-renewing neuroepithelial-like stem cells [49], which supports the potential role for miR-181a in regulating development of mDA neurons. While this may seem counter intuitive, it is important to distinguish been the specification of mDA neurons and their later morphological development.…”

MicroRNAs as biomarkers in molecular diagnosis of refractory epilepsy

“…Consequently, detecting the nuclear expression of miR-92a, miR-637 and miR-665 may be a useful method for epilepsy diagnosis. Furthermore, 16 miRNAs involved in epileptogenesis were identified by summarizing the meaningful results from many studies, including miRNAs modulating neuronal maturation (miR-137 [39]), neural cell proliferation in cortex (miR-9 [40], miR-124 [41,42], miR-137 [40,43], miR-184 [40,44,45] and let-7b [40,43,46]), and neural differentiation (miR-153 [47], miR-324 [47], miR-181a [47], miR-34a [27,48]). Other miRNAs are reported to be critical in neuronal migration (miR-9 [49], miR-134 [23], miR-137 [50]), neuronal differentiation (miR-125b [51] miR-137 [40]) and neural inflammation (miR-146a [52]).…”

5. Themenbereich Stammzellen: Aktuelle Entwicklungen der Stammzellforschung in Deutschland

“…Hinsichtlich der Optimierung der ES-Zell-Differenzierung in gewünschte Zelltypen berichtete die Gruppe um Oliver Brüstle am Institut für rekonstruktive Neurobiologie der Universität Bonn, dass die Mikro-RNAs miR-125b und miR-181a die Bildung dopaminerger Neurone 30 erleichtert, während miR-181a eine entgegengesetzte Funktion zeigt (Stappert et al, 2013). Mikro-RNAs sind kurze, konservierte, nicht-kodierende RNAs, die an der Genregulation beteiligt sind.…”