Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons.
Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the prolyl isomerase Pin1. We demonstrate that Pin1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, Pin1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by Pin1 or CRMP2A expression. Moreover, Pin1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover Pin1-catalyzed prolyl isomerization as a regulatory mechanism in axon guidance.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA; Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic; Institute of Physiology, Vídeňská 1083, 142 20 Prague 4, Czech Republic. Electronic address: martin.balastik@fgu.cas.cz.
Martin
M
Balastik
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
Xiao Zhen
XZ
Zhou
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA; Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Meritxell
M
Alberich-Jorda
Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic; Institute of Physiology, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Romana
R
Weissova
Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic; Institute of Physiology, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Jakub
J
Žiak
Department of Pediatric Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Maria F
MF
Pazyra-Murphy
Department of Pediatric Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Katharina E
KE
Cosker
Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Olga
O
Machonova
Institute of Molecular Genetics, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Iryna
I
Kozmikova
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
Chun-Hau
CH
Chen
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
Lucia
L
Pastorino
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
John M
JM
Asara
Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
Adam
A
Cole
Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
Calum
C
Sutherland
Department of Pediatric Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Rosalind A
RA
Segal
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA; Institute for Translational Medicine, Fujian Medical University, Fuzhou 350108, China. Electronic address: klu@bidmc.harvard.edu.
Kun Ping
KP
Lu
D000818:Animals; D001369:Axons / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; C576248:dpysl2b protein, zebrafish; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase