Faculty Collaboration Database

The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons. Mol Cell Neurosci 2015 Sep;68:272-83

Date

08/27/2015

Pubmed ID

26306672

Pubmed Central ID

PMC4832606

DOI

10.1016/j.mcn.2015.08.008

Scopus ID

2-s2.0-84940550850 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

Neurons in the embryonic and peripheral nervous system 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.

Author List

Simpson MT, Venkatesh I, Callif BL, Thiel LK, Coley DM, Winsor KN, Wang Z, Kramer AA, Lerch JK, Blackmore MG

Author

Murray Blackmore PhD Assistant Professor in the School of Allied Health department at Marquette University

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Axons
Central Nervous System
Fluoresceins
Gene Expression Regulation, Developmental
Homeodomain Proteins
Luminescent Proteins
Neurons
Rats
Rats, Sprague-Dawley
Transfection