Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling.
Synapse formation requires contact between dendrites and axons. Although this process is often viewed as axon mediated, dendritic filopodia may be actively involved in mediating synaptogenic contact. Although the signaling cues underlying dendritic filopodial motility are mostly unknown, brain-derived neurotrophic factor (BDNF) increases the density of dendritic filopodia and conditional deletion of tyrosine receptor kinase B (TrkB) reduces synapse number in vivo. Here, we report that TrkB associates with dendritic growth cones and filopodia, mediates filopodial motility, and does so via the phosphoinositide 3 kinase (PI3K) pathway. We used genetic and pharmacological manipulations of mouse hippocampal neurons to assess signaling downstream of TrkB. Conditional knock-out of two downstream negative regulators of TrkB signaling, Pten (phosphatase with tensin homolog) and Nf1 (neurofibromatosis type 1), enhanced filopodial motility. This effect was PI3K-dependent and correlated with synaptic density. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) was preferentially localized in filopodia and this distribution was enhanced by BDNF application. Thus, intracellular control of filopodial dynamics converged on PI3K activation and PIP3 accumulation, a cellular paradigm conserved for chemotaxis in other cell types. Our results suggest that filopodial movement is not random, but responsive to synaptic guidance molecules.
Luikart
Bryan W
BW
Department of Developmental Biology and Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390-9133, USA.
Zhang
Wei
W
Wayman
Gary A
GA
Kwon
Chang-Hyuk
CH
Westbrook
Gary L
GL
Parada
Luis F
LF
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D025542:Neurofibromin 1 / Q000235:genetics; D009924:Organ Culture Techniques; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D019208:Brain-Derived Neurotrophic Factor; D025542:Neurofibromin 1; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse