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Gustavo Paratcha

Publications and source records attributed to Gustavo Paratcha.

7 recordsLinked to original sources
PubMed2005

GDNF is a chemoattractant factor for neuronal precursor cells in the rostral migratory stream.

Olfactory bulb (OB) interneurons are generated from neuroblast cells derived from the anterior subventricular zone (SVZa) of the forebrain. The mechanisms guiding the rostral migration of these neuronal precursors are not well understood. Here, we show that glial cell line-derived neurotrophic factor (GDNF) is produced in the olfactory bulb but distributed along the rostral migratory stream (RMS) in a pattern concordant with the expression of its GPI-anchored receptor GFRalpha1. We demonstrate that GDNF is a chemoattractant factor for RMS-derived neuronal precursors, but not for SVZa neuroblast cells. In agreement with this, GDNF increased Cyclin-dependent kinase 5 (Cdk5) activity in RMS cells, a kinase critically involved in neuronal migration and guidance. GDNF-mediated cell chemoattraction was abrogated in RMS explants treated with the Cdk5 inhibitor Roscovitine as well as in RMS explants isolated from Ncam mutant mice. Chemical cross-linking assays showed that 125I-GDNF is able to interact directly with NCAM in RMS-derived cells. Taken together, these data demonstrate that GDNF is a direct chemoattractant factor for neuroblast cells migrating along the RMS and support the participation of NCAM during this guidance process.

Animals↗
PubMed2005

Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.

In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB(1) cannabinoid receptor (CB(1)R) 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 Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB(1)R 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.

Animals↗
PubMed2004

Disruption of EphA/ephrin-a signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine.

We have investigated functional roles of EphA/ephrin-A signaling in the development and function of the nigrostriatal system by overexpressing a soluble, broad-range EphA receptor antagonist in the central nervous system of transgenic mice. Adult transgenic mice showed a 30-40% reduction in the total volume of the substantia nigra (SN) without detectable differences in the number of dopaminergic neurons. Using fluorogold retrograde tracing from the striatum, we detected a 40-50% reduction in the number of dopaminergic neurons that could be traced from this structure in transgenic mice, suggesting that, a lower proportion of these cells were able to reach the striatum after disruption of EphA/ephrin-A signaling. In spite of this, total dopamine content in the striatum of transgenic mice was comparable to wild type. Analysis of locomotor activity and its regulation by pharmacological treatments that stimulate dopaminergic transmission revealed an unexpected dissociation of the behavioral responses to amphetamine and cocaine. In particular, transgenic mice were relatively insensitive to amphetamine while retaining normal responsiveness to cocaine, which, to the best of our knowledge, represents the first report of a dissociation of the behavioral responses to these two psychostimulants. Together, these results reveal an unexpected role for EphA/ephrin-A signaling in the normal connectivity and function of midbrain dopaminergic neurons.

Amphetamine↗
PubMed2003

The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands.

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.

Animals↗
PubMed2002

Target-derived GFRalpha1 as an attractive guidance signal for developing sensory and sympathetic axons via activation of Cdk5.

Immobilized and diffusible molecular cues regulate axon guidance during development. GFRalpha1, a GPI-anchored receptor for GDNF, is expressed as both membrane bound and secreted forms by accessory nerve cells and peripheral targets of developing sensory and sympathetic neurons during the period of target innervation. A relative deficit of GFRalpha1 in developing axons allows exogenous GFRalpha1 to capture GDNF and present it for recognition by axonal c-Ret receptors. Exogenous GFRalpha1 potentiates neurite outgrowth and acts as a long-range directional cue by creating positional information for c-Ret-expressing axons in the presence of a uniform concentration of GDNF. Soluble GFRalpha1 prolongs GDNF-mediated activation of cyclin-dependent kinase 5 (Cdk5), an event required for GFRalpha1-induced neurite outgrowth and axon guidance. Together with GDNF, target-derived GFRalpha1 can function in a non-cell-autonomous fashion as a chemoattractant cue with outgrowth promoting activity for peripheral neurons.

Animals↗
PubMed2002

Lipid rafts and the control of neurotrophic factor signaling in the nervous system: variations on a theme.

Lipid rafts are specialized, liquid-ordered subdomains of the plasma membrane. Through their ability to promote specific compartmentalization of lipids and membrane proteins, lipid rafts have emerged as membrane platforms specialized for signal transduction. In recent years, signaling by neurotrophic factors and their receptors has been shown to depend upon the integrity and function of lipid rafts and associated components. It has also been shown that these microdomains play critical roles in selective axon-dendritic sorting and the proteolytic processing of several neurotrophic ligands and receptors in neuronal cells. The available evidence supports an important role for lipid rafts in the initiation, propagation and maintenance of signal transduction events triggered by different neurotrophic factors and their receptors in the nervous system.

Animals↗