Intercellular communication involves either direct cell-cell contact or release and uptake of diffusible signals, two strategies mediated by distinct and largely nonoverlapping sets of molecules. Here, we show that the neural cell adhesion molecule NCAM can function as a signaling receptor for members of the GDNF ligand family. Association of NCAM with GFRalpha1, a GPI-anchored receptor for GDNF, downregulates NCAM-mediated cell adhesion and promotes high-affinity binding of GDNF to p140(NCAM), resulting in rapid activation of cytoplasmic protein tyrosine kinases Fyn and FAK in cells lacking RET, a known GDNF signaling receptor. GDNF stimulates Schwann cell migration and axonal growth in hippocampal and cortical neurons via binding to NCAM and activation of Fyn, but independently of RET. These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor.

Although both c-Ret and GFRalpha1 are required for responsiveness to GDNF, GFRalpha1 is widely expressed in the absence of c-Ret, suggesting alternative roles for "ectopic" sites of GFRalpha1 expression. We show that GFRalpha1 is released by neuronal cells, Schwann cells, and injured sciatic nerve. c-Ret stimulation in trans by soluble or immobilized GFRalpha1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRalpha1 mediates robust recruitment of c-Ret to lipid rafts via a novel mechanism requiring the c-Ret tyrosine kinase. Activated c-Ret associates with different adaptor proteins inside and outside lipid rafts. These results provide an explanation for the tissue distribution of GFRalpha1, supporting the physiological importance of c-Ret activation in trans as a novel mechanism to potentiate and diversify the biological responses to GDNF.

In utero exposure to ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie ⌬ 9 -THC-induced cognitive impairments, the neuronal basis of ⌬ 9 -THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB 1 cannabinoid receptor (CB1R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal ⌬ 9 -THC stimulation of CB1Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB 1R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.corticogenesis ͉ drug abuse ͉ neurotrophin E ndogenous cannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), modulate synaptic plasticity by the retrograde control of neurotransmitter release (1). Accordingly, a compartmentalization of endocannabinoid (eCB) synthesis and action has been demonstrated in adult brain (1-3). eCBs are predominantly synthesized in dendritic compartments and signal through presynaptic G i/o protein-coupled CB 1 cannabinoid receptors (CB 1 Rs) (4-6). The adult phenotype of cannabinoid systems is achieved through a series of developmentally regulated events culminating in high CB 1 R expression on cholecystokinin (CCK)-containing GABAergic interneurons (CB 1 R ϩ cells) in the hippocampus and neocortex (3,5,6).Recent studies have demonstrated the existence of functional CB 1 Rs in developing cortical neurons (7). A coincidence of eCB synthesis and release and CB 1 R activation within axonal growth cones was postulated to provide an eCB-driven reinforcement loop that regulates axonal growth and guidance (8). Although the functional significance of CB 1 Rs during assembly of cortical neuronal circuitries is unknown, their developmental impact is illustrated by long-lasting cognitive, motor, and social disturbances in offspring exposed prenatally to cannabis (9, 10).The majority of cortical interneurons are derived from extracortical precursor pools and undergo long-distance migration before inhabiting specific cortical layers (11, 12). Interneuron specification is in part governed by epigenetic cues within the neocortex, including brain-derived neurotrophic factor (BDNF) (12-14). Considering that pyramidal cells in the juvenile neocortex harbor the capacity of eCB synthesis and release (15), we hypothesiz...