GDF10 is a signal for axonal sprouting and functional recovery after stroke.
Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and differentiation factor 10 (GDF10) is induced in peri-infarct neurons in mice, non-human primates and humans. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFβRI and TGFβRII signaling. Using pharmacogenetic gain- and loss-of-function studies, we found that GDF10 produced axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocked axonal sprouting and reduced recovery. RNA sequencing from peri-infarct cortical neurons revealed that GDF10 downregulated PTEN, upregulated PI3 kinase signaling and induced specific axonal guidance molecules. Using unsupervised genome-wide association analysis of the GDF10 transcriptome, we found that it was not related to neurodevelopment, but may partially overlap with other CNS injury patterns. Thus, GDF10 is a stroke-induced signal for axonal sprouting and functional recovery.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Songlin
S
Li
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.|Neuroscience Interdepartmental Graduate Program, University of California Los Angeles, Los Angeles, California, USA.
Esther H
EH
Nie
Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts, USA.
Yuqin
Y
Yin
Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts, USA.
Larry I
LI
Benowitz
Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Spencer
S
Tung
Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Harry V
HV
Vinters
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA.
F Rena
FR
Bahjat
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA.
Mary P
MP
Stenzel-Poore
Riki
R
Kawaguchi
Giovanni
http://orcid.org/0000-0003-2105-1061
G
Coppola
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
S Thomas
ST
Carmichael
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D055413:Growth Differentiation Factor 10 / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020127:Recovery of Function / Q000502:physiology*; D012189:Retrospective Studies; D020521:Stroke / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
C525785:GDF10 protein, human; D055413:Growth Differentiation Factor 10