title: Axonal Degeneration Is Regulated by a Transcriptional Program that Coordinates Expression of Pro- and Anti-degenerative Factors.
abstract: Developmental neuronal cell death and axonal elimination are controlled by transcriptional programs, of which their nature and the function of their components remain elusive. Here, we identified the dual specificity phosphatase Dusp16 as part of trophic deprivation-induced transcriptome in sensory neurons. Ablation of Dusp16 enhanced axonal degeneration in response to trophic withdrawal, suggesting that it has a protective function. Moreover, axonal skin innervation was severely reduced while neuronal elimination was increased in the Dusp16 knockout. Mechanistically, Dusp16 negatively regulates the transcription factor p53 and antagonizes the expression of the pro-degenerative factor, Puma (p53 upregulated modulator of apoptosis). Co-ablation of Puma with Dusp16 protected axons from rapid degeneration and specifically reversed axonal innervation loss early in development with no effect on neuronal deficits. Overall, these results reveal that physiological axonal elimination is regulated by a transcriptional program that integrates regressive and progressive elements and identify Dusp16 as a new axonal preserving factor.
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Maor-Nof
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Romi
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Sar Shalom
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ulisse
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Calanit
authors.initials: C
authors.lastname: Raanan
authors.affiliation: Hazyar Zvi Shur 27 Petach Tikva 4921041, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Nof
authors.affiliation: Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dena
authors.initials: D
authors.lastname: Leshkowitz
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: avraham.yaron@weizmann.ac.il.
authors.forename: Avraham
authors.initials: A
authors.lastname: Yaron
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D005727:Ganglia, Spinal / Q000166:cytology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C438002:Dusp16 protein, mouse
keywords: Dusp16; NGF; Puma; axon degeneration; axon pruning; cell death; neurotrophin; p53