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    • Another remarkable observation of this study

    2018-11-08

    Another remarkable observation of this study is that ASCL1-iN dna-pk pathway are exclusively excitatory. This is surprising, because ASCL1 is not typically associated with the excitatory neuronal lineage during neural development (Bertrand et al., 2002; Fode et al., 2000; Guillemot et al., 1993; Johnson et al., 1990; Kim et al., 2008). In the forebrain, ASCL1 is predominantly expressed in the ventral medial and lateral ganglionic eminences (Guillemot et al., 1993; Lo et al., 1991). In Ngn2−/− mice, ASCL1 is ectopically overexpressed dorsally where also inhibitory marker genes such as Dlx2 and Gad67 are induced (Fode et al., 2000). These data suggested that ASCL1 acts as an important instructive signal for the inhibitory lineage, and one might have expected that ASCL1 would induce the inhibitory neuronal lineage in fibroblasts and ESCs. However, our results clearly demonstrate that ASCL1 may be permissive for generating inhibitory neurons but alone is clearly not instructive. Its instructive function does require other factors that are present in the cellular context of a neural progenitor cell. Our study also sheds light into the intriguing functional differences of the closely related proneural bHLH transcription factors NGN2 and ASCL1. While genetic swap experiments in vivo showed only modest factor-specific effects suggesting that both genes are functionally very similar (Parras et al., 2002), as reprogramming factors the two genes showed drastic differences. For example, in mouse fibroblasts, ASCL1 is a powerful reprogramming factor, but NGN2 alone is not able to induce neuronal features, presumably due to insufficient induction of Myt1l. In human ESCs, on the other hand, previous work suggested that ASCL1 is incapable of efficient neuronal reprogramming, whereas NGN2 and NEUROD1 are extremely effective in generating mature neurons within a matter of days (Pang et al., 2011; Zhang et al., 2013). It was unclear whether this mutually exclusive role is dependent of the species (mouse versus human) or the cell type (fibroblasts versus pluripotent cells). In this paper, we have clarified this question and come to the conclusion that the different effects of ASCL1 versus NGN2 are cell-context dependent. First, we report the totally unexpected finding that ASCL1 alone can indeed convert human fibroblasts to iN cells that are even able to fire mature APs. Second, we tested ASCL1 and NGN2 side by side in murine ESCs and observed that also in this condition ASCL1 induces neurons slower (about 5 days for the first appearance of neuronal morphologies) than NGN2 (about 2 days for first neuronal morphologies) (see also: Thoma et al., 2012; Yamamizu et al., 2013).
    Experimental Procedures
    Author Contributions
    Acknowledgments C.E.A. was supported by a California Institute of Regenerative Medicine training grant (TGR-01159), J.D. by a Child Health Research Institute postdoctoral fellowship (Lucile Packard Foundation, UL1-TR001085), C.P. by a fellowship from the National Institute of Child Health and Human Development (1F32HD078051-01), M.M. by a fellowship from the German Research Foundation (DFG), Q.Y.L. by the Agency for Science, Technology and Research (A∗STAR, Singapore), and H.A. by a fellowship from the Swedish Research Council and the Swedish Society for Medical Research. This study was funded by NIH grants R01 MH092931 and AG010770-18A1 (to M.W. and T.C.S.). M.W. is supported by the Tashia and John Morgridge Faculty Scholar Fund, Child Health Research Institute at Stanford and a New York Stem Cell Foundation-Robertson Investigator Award.
    Introduction Spinal muscular atrophy with respiratory distress type 1 (SMARD1, OMIM 604320), also identified as distal spinal muscular atrophy type 1 (DSMA1), is an autosomal recessive motor neuron disorder and the second most frequent form of spinal muscular atrophy after spinal muscular atrophy (SMA) 5q. SMARD1 is characterized by a sudden onset of respiratory distress, usually within the first year of life, with initially distal and later generalized muscle weakness (Eckart et al., 2012). SMARD1 results from mutations in the gene encoding the immunoglobulin microbinding protein 2 (IGHMBP2), which encodes an ATPase/helicase that belongs to the SF1 superfamily (Grohmann et al., 2001; Guenther et al., 2009; Jankowsky et al., 2011). A splice-site mutation in murine Ighmbp2 causes a neuromuscular disorder similar to the human disease in the nmd mouse, representing the animal model of SMARD1 (Cox et al., 1998). How these molecular abnormalities lead to motor neuron degeneration and the disease phenotype in rodents and humans is unknown.