Fly heads were homogenized and centrifuged at 800× g to pellet debris. The supernatant was incubated with 0.3 units biotinylated-phalloidin (Molecular Probes, Eugene, OR, USA) followed by precipitation with streptavidin-coupled Dynabeads (Invitrogen). To control for nonspecific protein interactions, the same protocol was followed with biotin in place of biotinylated

phalloidin. Flies were 1-day-old in all coprecipitations. Samples were analyzed by 15% SDS-PAGE and immunoblotted in accordance with standard protocols. All immunoblots were repeated at least three times with similar results. See Supplemental Experimental Procedures for detailed methods. We thank W. Dynan Bortezomib cost and T. Schwarz for providing cDNAs. The rTg4510 mice were a generous gift of Bradley Hyman. T. Schwarz, E. Schejter, and H. Bellen kindly provided Drosophila stocks. D. Rennie at the Cutaneous Biology Research Center at Massachusetts General Hospital performed

embryo injections to create transgenic strains. Confocal microscopy was performed at the Harvard Neurodiscovery Center Optical Imaging Facility. We thank T. Fulga and M. Colaiácovo for helpful discussions. The work was supported by grants from the NIA, the American Health Assistance IDH inhibitor Foundation, and the Ellison Medical Foundation to M.B.F., the NIA to B.D., and the Clem Jones Foundation to J.G. “
“How transcription factors control cellular plasticity and maintain differentiation is currently of great interest, inspired by the success of experimental reprogramming, where remarkable phenotypic transitions can be induced by enforced expression

of fate determining factors (Zhou and Melton, 2008). These findings raise a key question: to what extent are natural transitions in the state of differentiated cells also governed by specific transcription factors? Such phenotypic transitions are seen in tumorigenesis, dedifferentiation and transdifferentiation. They are also fundamental to tissue repair and regeneration, and in regenerative systems, a major focus of work is identification of gene programs that are selectively activated after injury and which impact the repair process. The striking ADP ribosylation factor regenerative capacity of the PNS rests on the surprising plasticity of Schwann cells, and the ability of these cells to switch between differentiation states, a feature that is highly unusual in mammals (Jessen and Mirsky, 2005, 2008; Jopling et al., 2011). In a process reminiscent of the radical injury responses of zebrafish cardiomyocytes or pigment cells of the newt iris, nerve injury, and loss of axonal contact causes mammalian Schwann cells to lose their differentiated morphology, downregulate myelin genes, upregulate markers of immature Schwann cells, and re-enter the cell cycle. This radical process of natural dedifferentiation has few if any parallels in mammalian systems.