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The Journal of Neuroscience, March 15, 1999, 19(6):2069-2080
Differential Sorting of Nerve Growth Factor and Brain-Derived
Neurotrophic Factor in Hippocampal Neurons
S. Javad
Mowla1,
Sangeeta
Pareek1,
Hooman F.
Farhadi1,
Kevin
Petrecca3,
James P.
Fawcett1,
Nabil G.
Seidah4,
Stephen J.
Morris1,
Wayne S.
Sossin2, and
Richard A.
Murphy1
1 Centre for Neuronal Survival, 2 Cell
Biology of Excitable Tissues Group, Department of Neurology and
Neurosurgery, Montreal Neurological Institute,
3 Department of Physiology, McGill University, Montreal,
Quebec, Canada H3A 2B4, and 4 Laboratory of Biochemical
Neuroendocrinology, Clinical Research Institute of Montreal, Montreal,
Quebec, Canada H2W 1R7
Nerve growth factor (NGF) is released through the constitutive
secretory pathway from cells in peripheral tissues and nerves where it
can act as a target-derived survival factor. In contrast, brain-derived
neurotrophic factor (BDNF) appears to be processed in the regulated
secretory pathway of brain neurons and secreted in an
activity-dependent manner to play a role in synaptic plasticity. To
determine whether sorting differences are intrinsic to the neurotrophins or reflect differences between cell types, we compared NGF and BDNF processing in cultured hippocampal neurons using a
Vaccinia virus expression system. Three independent criteria (retention
or release from cells after pulse-chase labeling,
depolarization-dependent release, and immunocytochemical localization)
suggest that the bulk of newly synthesized NGF is sorted into the
constitutive pathway, whereas BDNF is primarily sorted into the
regulated secretory pathway. Similar results occurred with AtT 20 cells, including those transfected with cDNAs encoding neurotrophin
precursor-green fluorescent protein fusions. The NGF precursor, but
not the BDNF precursor, is efficiently cleaved by the endoprotease
furin in the trans-Golgi network (TGN). Blocking furin
activity in AtT 20 cells with  1-PDX as well as increasing the
expression of NGF precursor partially directed NGF into the regulated
secretory pathway. Therefore, neurotrophins can be sorted into either
the constitutive or regulated secretory pathways, and sorting may be
regulated by the efficiency of furin cleavage in the TGN. This mechanism may explain how neuron-generated neurotrophins can act both
as survival factors and as neuropeptides.
Key words:
NGF; BDNF; precursor; furin; constitutive secretion; regulated secretion; neurotrophin
Copyright © 1999 Society for Neuroscience 0270-6474/99/1962069-12$05.00/0
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