Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3

Yonglin Gao; George Z Wei; Michael D Forston; Benjamin Rood; Emily R Hodges; Darlene Burke; Kariena Andres; Johnny Morehouse; Christine Armstrong; Charles Glover; Lukasz P Slomnicki; Jixiang Ding; Julia H Chariker; Eric C Rouchka; Sujata Saraswat Ohri; Scott R Whittemore; Michal Hetman

doi:10.1038/s41598-023-36258-2

Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3

Sci Rep. 2023 Jun 6;13(1):9193. doi: 10.1038/s41598-023-36258-2.

Authors

Yonglin Gao^{1

2}, George Z Wei^{1

3

4}, Michael D Forston^{1

5}, Benjamin Rood^{1

6}, Emily R Hodges^{1

2}, Darlene Burke^{1

2}, Kariena Andres^{1

2}, Johnny Morehouse^{1

2}, Christine Armstrong^{1

2}, Charles Glover¹, Lukasz P Slomnicki^{1

2}, Jixiang Ding^{1

7}, Julia H Chariker⁸, Eric C Rouchka⁸, Sujata Saraswat Ohri^{1

2}, Scott R Whittemore^{1

2

5

3

6}, Michal Hetman^{9

10

11

12

13}

Affiliations

¹ Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 S. Floyd St., MDR616, Louisville, KY, 40202, USA.
² Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
³ Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
⁴ MD/PhD Program, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
⁵ Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
⁶ Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
⁷ Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, 40292, USA.
⁸ Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, 40292, USA.
⁹ Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 S. Floyd St., MDR616, Louisville, KY, 40202, USA. michal.hetman@louisville.edu.
¹⁰ Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. michal.hetman@louisville.edu.
¹¹ Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. michal.hetman@louisville.edu.
¹² Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. michal.hetman@louisville.edu.
¹³ Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA. michal.hetman@louisville.edu.

Abstract

The integrated stress response (ISR)-activated transcription factors ATF4 and CHOP/DDIT3 may regulate oligodendrocyte (OL) survival, tissue damage and functional impairment/recovery in white matter pathologies, including traumatic spinal cord injury (SCI). Accordingly, in OLs of OL-specific RiboTag mice, Atf4, Chop/Ddit3 and their downstream target gene transcripts were acutely upregulated at 2, but not 10, days post-contusive T9 SCI coinciding with maximal loss of spinal cord tissue. Unexpectedly, another, OL-specific upregulation of Atf4/Chop followed at 42 days post-injury. However, wild type versus OL-specific Atf4^-/- or Chop^-/- mice showed similar white matter sparing and OL loss at the injury epicenter, as well as unaffected hindlimb function recovery as determined by the Basso mouse scale. In contrast, the horizontal ladder test revealed persistent worsening or improvement of fine locomotor control in OL-Atf4^-/- or OL-Chop^-/- mice, respectively. Moreover, chronically, OL-Atf^-/- mice showed decreased walking speed during plantar stepping despite greater compensatory forelimb usage. Therefore, ATF4 supports, while CHOP antagonizes, fine locomotor control during post-SCI recovery. No correlation between those effects and white matter sparing together with chronic activation of the OL ISR suggest that in OLs, ATF4 and CHOP regulate function of spinal cord circuitries that mediate fine locomotor control during post-SCI recovery.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Contusions* / pathology
Mice
Oligodendroglia / pathology
Recovery of Function / physiology
Spinal Cord / pathology
Spinal Cord Injuries*
Transcription Factor CHOP / genetics
Transcription Factors

Substances

Ddit3 protein, mouse
Transcription Factor CHOP
Transcription Factors
Atf4 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding