Signaling Endosomes Point the Way

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Science's STKE  10 Jul 2007:
Vol. 2007, Issue 394, pp. tw240
DOI: 10.1126/stke.3942007tw240

Brain-derived neurotrophic factor (BDNF) stimulates the migration of cerebellar granule cell precursors (GCPs) from the external granule layer to the internal granule layer. The movement of the GCPs is impaired in BDNF knockout mice. Zhou et al. isolated GCPs from postnatal day 6 (P6) mice and monitored their migration in culture in response to BDNF, applied uniformly or as a gradient. BDNF promoted the directional chemotaxis of the GCPs only when presented as a gradient. Although exogenously applied BDNF stimulated movement of GCPs from bdnf−/− mice, these cells lacked directional migration even in response to a gradient of BDNF, which suggests that an autocrine function for BDNF is also important for proper chemotaxis. To understand how autocrine BDNF may contribute to directional movement, cultured GCPs were stimulated with a related neurotrophin NT4, which also stimulates the TrkB receptor, and BDNF was found to be secreted, which could amplify the BDNF gradient and thus contribute to directional migration. GCPs have two receptors for BDNF: TrkB and p75NTR. BDNF-induced chemotaxis (in cultured cells and organotypic slices) was blocked if the TrkB receptor activity was inhibited but was unaffected in cells defective for p75NTR signaling. In the cultured GCPs, TrkB receptors colocalized with early endosomal markers at the leading edge toward the BDNF gradient, suggesting internalization of the receptor. In the P6 mouse cerebellum, TrkB was found in punctate structures that often colocalized with an endosomal marker; however, only in the wild-type mouse brains was TrkB consistently oriented toward the internal granule layer. Pharmacological inhibition of endocytosis inhibited cultured GCP migration toward a BDNF gradient, and impairment of dynamin function, which is required for clathrin-mediated endocytosis, blocked movement of GCPs from the external granule layer in organotypic slices. BDNF-induced GCP migration involved phosphoinositide 3-kinase (PI3K) signaling and activation of the Rac-specific guanine-nucleotide exchange factor Tiam1 (based on pharmacological inhibition and siRNA knockdown experiments). Thus, BDNF-induced migration appears to involve both the formation of oriented signaling endosomes and endogenous production of BDNF, which may amplify the BDNF gradient to promote motility (see Kaplan and Miller for commentary).

P. Zhou, M. Porcionatto, M. Pilapil, Y. Chen, Y. Choi, K. F. Tolias, J. B. Bikoff, E. J. Hong, M. E. Greenberg, R. A. Segal, Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55, 53-68 (2007). [PubMed]

D. R. Kaplan, F. D. Miller, Developing with BDNF: A moving experience. Neuron 55, 1-2 (2007). [PubMed]