Lineage reprogramming: a shortcut to generating functional neurons from fibroblasts.

A series of recent publications have shown that human fibroblasts can be directly converted to functional neurons using defined combinations of transcription factors. The resulting neurons are called induced neurons (iN). When compared with induced pluripotent stem (iPS) cell technology, where somatic cells can be reprogrammed to neurons via a pluripotent stem cell state, lineage reprogramming offers an appealing short cut to generate functional neurons from fibroblasts that has several advantages: the process is quicker, less laborious and does not involve a stem cell intermediate. Thus, the generation of iNs opens up new and exciting possibilities for generating patientand/or disease-specific neurons for disease modeling and brain repair. Generation of dopamine (DA) neurons using direct conversion is of particular interest due to their involvement in Parkinson disease (PD). By tailoring the cocktail of conversion factors to include DA neuron fate determinants, iN cells expressing genes and proteins characteristic of dopamine neurons can be formed from mouse and human fibroblasts. Dopaminergic iN cells can be obtained from fibroblasts using different sets of transcription factors (Ascl1, Brn2, Myt1l, FoxA2 and Lmx1a or Ascl1, Nurr1 and Lmx1a). Both transcription factor cocktails give rise to DA-iNs displaying functional properties of DA neurons in vitro, as demonstrated by whole-cell patch clamp recordings showing spontaneous action potentials, including pacemaker-like activity and potassium-evoked DA release (summarized in Fig. 1A). Lineage reprogramming A shortcut to generating functional neurons from fibroblasts