title: The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons.
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.
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Matthew T
authors: MT
authors: Simpson
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Ishwariya
authors: I
authors: Venkatesh
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Ben L
authors: BL
authors: Callif
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Laura K
authors: LK
authors: Thiel
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Denise M
authors: DM
authors: Coley
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Kristen N
authors: KN
authors: Winsor
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Zimei
authors: Z
authors: Wang
authors: Marquette University, Department of Biomedical Sciences, 53201, United States.
authors: Audra A
authors: AA
authors: Kramer
authors: The Ohio State University, The Center for Brain and Spinal Cord Repair, The Department of Neuroscience, 43210, United States.
authors: Jessica K
authors: JK
authors: Lerch
authors: Marquette University, Department of Biomedical Sciences, 53201, United States. Electronic address: murray.blackmore@marquette.edu.
authors: Murray G
authors: MG
authors: Blackmore
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology*; D005452:Fluoresceins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D005452:Fluoresceins; C513079:Hhex protein, rat; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; C007740:fluorexon
keywords: Axon regeneration; High content screening; Transcription factor