Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics.
Neurons differ in their responses to injury, but the underlying mechanisms remain poorly understood. Using quantitative proteomics, we characterized the injury-triggered response from purified intact and axotomized retinal ganglion cells (RGCs). Subsequent informatics analyses revealed a network of injury-response signaling hubs. In addition to confirming known players, such as mTOR, this also identified new candidates, such as c-myc, NFκB, and Huntingtin. Similar to mTOR, c-myc has been implicated as a key regulator of anabolic metabolism and is downregulated by axotomy. Forced expression of c-myc in RGCs, either before or after injury, promotes dramatic RGC survival and axon regeneration after optic nerve injury. Finally, in contrast to RGCs, neither c-myc nor mTOR was downregulated in injured peripheral sensory neurons. Our studies suggest that c-myc and other injury-responsive pathways are critical to the intrinsic regenerative mechanisms and might represent a novel target for developing neural repair strategies in adults.
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Stephane
S
Belin
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Homaira
H
Nawabi
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Chen
C
Wang
Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Shaojun
S
Tang
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Alban
A
Latremoliere
Department of Urology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Peter
P
Warren
Department of Developmental Pathology, University of Bonn Medical School, Sigmund Freud Strasse 25, 53127 Bonn, Germany.
Hubert
H
Schorle
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Ceren
C
Uncu
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Clifford J
CJ
Woolf
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zhigang.he@childrens.harvard.edu.
Zhigang
Z
He
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: judith.steen@childrens.harvard.edu.
Judith A
JA
Steen
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D019771:Axotomy / Q000379:methods; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D020221:Optic Nerve Injuries / Q000378:metabolism*; D040901:Proteomics; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology