TY - JOUR TI - Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons AU - Herdy, Joseph AU - Schafer, Simon AU - Kim, Yongsung AU - Ansari, Zoya AU - Zangwill, Dina AU - Ku, Manching AU - Paquola, Apua AU - Lee, Hyungjun AU - Mertens, Jerome AU - Gage, Fred H A2 - Bronner, Marianne E A2 - Rubin, Lee L A2 - Karow, Marisa VL - 8 PY - 2019 DA - 2019/05/17 SP - e41356 C1 - eLife 2019;8:e41356 DO - 10.7554/eLife.41356 UR - https://doi.org/10.7554/eLife.41356 AB - Direct conversion of human somatic fibroblasts into induced neurons (iNs) allows for the generation of functional neurons while bypassing any stem cell intermediary stages. Although iN technology has an enormous potential for modeling age-related diseases, as well as therapeutic approaches, the technology faces limitations due to variable conversion efficiencies and a lack of thorough understanding of the signaling pathways directing iN conversion. Here, we introduce a new all-in-one inducible lentiviral system that simplifies fibroblast transgenesis for the two pioneer transcription factors, Ngn2 and Ascl1, and markedly improves iN yields. Further, our timeline RNA-Seq data across the course of conversion has identified signaling pathways that become transcriptionally enriched during iN conversion. Small molecular modulators were identified for four signaling pathways that reliably increase the yield of iNs. Taken together, these advances provide an improved toolkit for iN technology and new insight into the mechanisms influencing direct iN conversion. KW - direct reprogramming KW - iN KW - transgenesis KW - pathway analysis KW - lentivirus KW - induced neurons JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -