The tumor suppressor HHEX restricts axon growth in central nervous system neurons

Society for Neuroscience Chicago 2015

Poster 568. Central Nervous System Regeneration
Location: Hall A
Time: Tuesday, October 20, 2015, 1:00 PM – 5:00 PM
Program#/Poster#: 568.12/A55
Topic: A.07. Transplantation and Regeneration
Support: The Bryon Riesch Paralysis Foundation
SCIS/Unite 2 Fight Paralysis

Title: The tumor suppressor HHEX restricts axon growth in central nervous system neurons

Authors: *M. SIMPSON1, I. VENKATESH1, B. CALLIF1, L. THIEL1, D. COLEY1, K. WINSOR1, Z. WANG1, J. LERCH2, M. G. BLACKMORE1; 1Marquette Univ., Milwaukee, WI; 2The Ctr. for Brain and Spinal Cord Repair, The Ohio State Univ., Columbus, OH

Abstract: Neurons in the 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. We and others have shown previously that activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the underlying transcription factors. In order to identify novel regulators of axon regeneration, we employed high content assays of neurite outgrowth, testing sixty-nine transcription factors that have been previously associated with cellular growth and motility in non-neuronal systems. This screen revealed two novel transcription factors (E2F1 and YAP1) as growth promoting, and four (PITX1, RBM14, ZBTB16, and HHEX) as growth inhibiting. Follow-up experiments focused on HHEX, the most potent and consistent growth inhibitor. Immunohistochemistry with axonspecific Tau1 antibodies showed that HHEX overexpression in cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. Although HHEX is unstudied in the CNS, we used immunohistochemistry and western blotting to show that HHEX is widely expressed in CNS neurons, including corticospinal tract neurons after spinal injury. Intriguingly, peripheral neurons lack native HHEX, and forced overexpression of native HHEX restricted axon growth potential in DRG neurons. These findings suggest a role for HHEX in limiting the regenerative capacity of mature CNS neurons.

Disclosures: M. Simpson: None. I. Venkatesh: None. B. Callif: None. L. Thiel: None. D. Coley: None. K. Winsor: None. Z. Wang: None. J. Lerch: None. M.G. Blackmore: None.

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