Document Type
Article
Language
eng
Format of Original
12 p.
Publication Date
9-2015
Publisher
Elsevier
Source Publication
Molecular and Cellular Neuroscience
Source ISSN
1044-7431
Original Item ID
DOI: 10.1016/j.mcn.2015.08.008
Abstract
Neurons in the embryonic and peripheral nervoussystem respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments are focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present only in trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension.
Recommended Citation
Simpson, Matthew T.; Venkatesh, Ishwariya; Callif, Ben L.; Thiel, Laura K.; Coley, Denise M.; Winsor, Kristen N.; Wang, Zimei; Kramer, Audra A.; Lerch, Jessica K.; and Blackmore, Murray G., "The Tumor Suppressor HHEX Inhibits Axon Growth when Prematurely Expressed in Developing Central Nervous System Neurons" (2015). Biological Sciences Faculty Research and Publications. 515.
https://epublications.marquette.edu/bio_fac/515
Comments
Accepted version. Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI. © 2015 Elsevier Inc. Used with permission.
NOTICE: this is the author’s version of a work that was accepted for publication in Molecular and Cellular Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI.