TY - JOUR
T1 - Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration
AU - Farley, Jonathan E.
AU - Burdett, Thomas C.
AU - Barria, Romina
AU - Neukomm, Lukas J.
AU - Kenna, Kevin P.
AU - Landers, John E.
AU - Freeman, Marc R.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank all M.R.F. laboratory members and colleagues in the field for feedback, comments, and suggestions; Jaeda Coutinho-Budd for her technical assistance in confocal image acquisition well as her scientific input and skilled editorial assistance; Dr. Maninjay Atianand for assistance with ChIP; and Amy Sheehan for generating the 5XUAS::5XMyc vector. Deficiency lines screened in this study were generated through a collaboration with the laboratories of Dr. Chris Doe and Dr. Tory Herman from the University of Oregon. Sequencing was performed at the Bauer Core Facility at Harvard University. This work was supported by National Institute of Neurological Disorders and Stroke Grant R01 NS053538 (to M.R.F.). During the period of this study, M.R.F. was an Investigator with the Howard Hughes Medical Institute and J.E.L. was a collaborating PI.
PY - 2018/2/6
Y1 - 2018/2/6
N2 - Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the Drosophila C2H2 zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/ RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
AB - Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the Drosophila C2H2 zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/ RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
KW - Axon death
KW - Axons
KW - Wallerian degeneration
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U2 - 10.1073/pnas.1715837115
DO - 10.1073/pnas.1715837115
M3 - Article
C2 - 29295933
AN - SCOPUS:85041427212
SN - 0027-8424
VL - 115
SP - 1358
EP - 1363
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -