Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors.
During development, neural precursors migrate in response to positional cues such as growth factor gradients. However, the mechanisms that enable precursors to sense and respond to such gradients are poorly understood. Here we show that cerebellar granule cell precursors (GCPs) migrate along a gradient of brain-derived neurotrophic factor (BDNF), and we demonstrate that vesicle trafficking is critical for this chemotactic process. Activation of TrkB, the BDNF receptor, stimulates GCPs to secrete BDNF, thereby amplifying the ambient gradient. The BDNF gradient stimulates endocytosis of TrkB and associated signaling molecules, causing asymmetric accumulation of signaling endosomes at the subcellular location where BDNF concentration is maximal. Thus, regulated BDNF exocytosis and TrkB endocytosis enable precursors to polarize and migrate in a directed fashion along a shallow BDNF gradient.
Zhou
Pengcheng
P
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Porcionatto
Marimelia
M
Pilapil
Mariecel
M
Chen
Yicheng
Y
Choi
Yoojin
Y
Tolias
Kimberley F
KF
Bikoff
Jay B
JB
Hong
Elizabeth J
EJ
Greenberg
Michael E
ME
Segal
Rosalind A
RA
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000502:physiology*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein