期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 27, 页码 7006-7012出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0195-08.2008
关键词
BDNF; TrkB; filopodia; spine; PIP3; PIP2
资金
- NIMH NIH HHS [MH46613, R37 MH046613, F32 MH079548, F32MH079548, R01 MH046613] Funding Source: Medline
- NINDS NIH HHS [R37NS33199, P50 NS052606-04, P50 NS052606, P50 NS 052606, R37 NS033199] Funding Source: Medline
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.
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