The ability to reprogram human fibroblasts to neurons in vitro has opened up unprecedented opportunities in disease modelling and cellular therapeutics. Despite this breakthrough, a major challenge in the field is the limited phenotypic and functional maturation of the induced neurons (iNs). Now, on p. , Anna Philpott and colleagues report that cell cycle-dependent phosphorylation of key neural determinant Ascl1 affects neuronal maturation both in vivo during Xenopus development and in vitro during reprogramming of human fibroblasts to iNs. The authors show that Ascl1 can undergo phosphorylation at multiple serine-proline sites, and that this multisite phosphorylation represents a means to limit neurogenesis to appropriate levels during development. Disruption of this mechanism using a phosphomutant form of Ascl1 results in enhanced neuronal production in the early Xenopus embryo. Moreover, substitution of the phosphomutant Ascl1 for wild-type Ascl1 during lineage reprogramming not only increases the efficiency of conversion to iNs in the absence of reprogramming factor NeuroD, but also enhances the morphological and functional maturation of the cells. This exciting study suggests a way forward in addressing the roadblock of functional maturation during direct lineage reprogramming in vitro.
