Two microRNAs, miR-23 and miR-125, control the cell fate determinant Musashi1, during astrocyte differentiation
During nervous system development neural progenitor cells (NPCs) first generate neuronal cell types and then glial cells (astrocytes and oligodendrocytes). So far, the molecular pathways that instruct NPC to turn off neurogenesis and turn on gliogenesis remain elusive. microRNAs (miRNAs) are good candidates for directing such temporarily regulated switch but, so far, only miRNA-dependent regulatory circuitries controlling neuronal and oligodendrocytic differentiation have been elucidated. Astrocytes, besides having a role in synapses formation and neuronal maturation are key players in the pathogenesis of CNS disorders such as Alzheimer and ALS. It is, therefore, crucial to identify the miRNAs and the regulatory circuitries important for astrocyte specification and terminal differentiation.
By large-scale expression profiling, we produced an atlas of miRNAs modulated during the differentiation of astrocytes generated from mouse NPCs. Among the miRNAs whose expression was strongly upregulated during in vitro astrocyte-specific differentiation, we focused on miR-23, previously described as astrocyte-enriched miRNA, and miR-125 that has been recently found to be involved in neural lineage commitment of human embryonic stem cells.
By gain-of-function approach, we demonstrated that miR-23 and miR-125 mediate the decrease of Msi1, an RNA binding protein with a critical function in stem cell maintenance and self renewal capability of NPCs. Remarkably, the transduction of miR-23 and miR-125 in NPCs via lentiviral vectors triggers the expression of the astrocyte differentiation marker GFAP,and inhibits cell proliferation rate, suggesting a role for these miRNAs in the commitment of NPCs towards the astroglial lineage.