A new recipe for serotonergic neurons

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Science Translational Medicine  18 Nov 2015:
Vol. 7, Issue 314, pp. 314ec197
DOI: 10.1126/scitranslmed.aad5908

How abnormal function of the serotonergic nervous system affects depression, anxiety, and other neuropsychiatric disorders remains unclear, partly because there have been no established methods to study human serotonergic neurons in culture. Now, two groups have independently discovered a way to induce the formation of serotonergic neurons from human skin fibroblasts (Vadodaria et al. and Xu et al.). Reassuringly, both strategies are similar, relying upon lentiviral vector delivery of an overlapping set of tetracycline-inducible genes encoding different transcription factors. The minimum gene set proposed by both groups encoded the following transcription factors: ASCL1, FEV, and LMX1B, as well as NGN2, NKX2.2, and GATA2 (Vadodaria et al.) or FOXA2, and a short-hairpin RNA to knockdown p53 (Xu et al.). Both groups report that they could enhance the yield of neurons further by culturing human skin fibroblasts during the early days of induction in the presence of dual-SMAD inhibitors, which are known to promote neuronal induction during pluripotent stem cell differentiation. Final optimization strategies differed between the groups, with Vadodaria et al. using puromycin selection to improve purity, and Xu et al. testing a panel of small molecules, microRNAs, and different oxygen conditions. Although quantified in different ways, both groups seem to have achieved comparable yields of 50 to 60% neurons. A substantial majority of these seemed to be serotonergic neurons. Integration of aspects of both protocols might increase the yield of serotonergic neurons still further.

Both groups then showed that the induced serotonergic neurons were functionally mature, capable of firing spontaneous action potentials and releasing serotonin in a manner that could be pharmacologically manipulated with citalopram, a selective serotonin reuptake inhibitor. Last, aided by a new lentiviral vector reporter that indicated serotonergic identity, Vadodaria et al. also compared global gene expression patterns between induced serotonergic neurons and induced neurons, finding that the former were enriched for genes expressed in the human midbrain raphe compared with the cerebral cortex.

The ability to induce serotonergic neurons from the skin fibroblasts of patients will enable development of new human cell–based models of neuropsychiatric disorders such as depression and anxiety, and should provide a better understanding of the pathogenesis of these disorders.

K. C. Vadodaria et al., Generation of functional human serotonergic neurons from fibroblasts. Mol. Psychiatry 10.1038/mp.2015.161 (2015). [Abstract]

Z. Xu et al., Direct conversion of human fibroblasts to induced serotonergic neurons. Mol. Psychiatry 10.1038/mp.2015.101 (2015). [Full Text]

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