title: Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery.
abstract: Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201.
authors.forename: Ashley
authors.initials: A
authors.lastname: Reynolds
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201.
authors.forename: Adam
authors.initials: A
authors.lastname: Kirry
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nienhaus
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201 murray.blackmore@marquette.edu.
authors.forename: Murray G
authors.initials: MG
authors.lastname: Blackmore
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D018737:Hand Strength / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D011712:Pyramidal Tracts / Q000473:pathology / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology*; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D008164:Luminescent Proteins; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse
keywords: Sox11; axon regeneration; gene therapy; spinal cord injury; transcription factor