Cellular/Molecular
Binding Netrin to Its Receptors
Robert P. Kruger, Jeeyong Lee, Weiquan Li, and Kun-Liang Guan
(see pages 10826-10834)
The intricate ballet of neuronal development and migration is choreographed by a troupe of attractant and repellant signaling molecules. Axonal growth cones express receptors that respond to gradients of these molecules that instruct them to extend, branch, and terminate properly. This week, Kruger et al. identify the molecular domains that govern interaction between the guidance molecule netrin-1 and its receptors DCC and Unc5. Netrin binding to DCC signals attraction, whereas binding to Unc5 alone, or at both receptors, signals repulsion through regulation of receptor tyrosine phosphorylation. In cultured cells, the authors expressed domain deletion mutants and found domains crucial to binding interactions between netrin and its receptors, as well as nonbinding domains that affected phosphorylation. For example, the netrin-binding domain in Unc5 appears to be autoinhibitory for receptor phosphorylation. Caenorhabditis elegans mutants expressing Unc5 receptors without binding or nonbinding domains indicated that both domain types were required for normal receptor function.
Development/Plasticity/Repair
PAK3 and Synaptic Development
Bernadett Boda, Stefano Alberi, Irina Nikonenko, Roxanne Node-Langlois, Pascal Jourdain, Marlyse Moosmayer, Lorena Parisi-Jourdain, and Dominique Muller
(see pages 10816-10825)
The X chromosome has become a hot spot for the discovery of genes causing mental retardation. One of these is the MRX30 mutation in p21-activated kinase 3 (PAK3). Mental retardation is sometimes marked by abnormal dendritic spine morphology, and recent analysis of a mouse deficient for PAK3 suggested a role in synapse formation and plasticity. This week, Boda et al. show that suppression of PAK3 expression affects dendritic spine morphogenesis. The authors cultured hippocampal slices from rat and transfected neurons with PAK3 small interfering RNA oligos or a dominant-negative PAK3 gene carrying the MRX30 mutation. Live confocal imaging showed that the transfected neurons had more elongated spines and filopodia-like protrusions but fewer mature synapses. Perhaps not surprisingly, cells expressing the MRX30 mutant PAK3 showed a reduction in long-term potentiation. The changes in dendritic morphology point to PAK3 as a regulator of synaptic function and may provide clues to the basis of the cognitive deficits associated with the MRX30 mutation.
Illustration of the spine morphology observed in cells cotransfected with enhanced green fluorescent protein and either an empty vector [control (Ctrl)], PAK3 MRX3 gene (MRX), or PAK3 carrying the Kdead mutation (Kdead). The arrows indicate elongated spines, and the asterisk indicates filopodia-like protrusions. See the article by Boda et al. for details.
Behavioral/Systems/Cognitive
Stress, Locomotion, and 5-HT1A Receptors
Qian Li, Andrew Holmes, Li Ma, Louis D. Van de Kar, Francisca Garcia, and Dennis L. Murphy
(see pages 10868-10877)
Serotonin pathways regulate behavioral responses to stress through the hypothalamic-pituitary-adrenal axis. Mice lacking the serotonin transporter (SERT) gene also display increased anxiety-related exploration and response to minor stress, accompanied by decreased hypothalamic expression of serotonin 1A receptors (5-HT1A). This week, Li et al. manipulate expression of hypothalamic 5-HT1A receptors to determine what behaviors require these receptors. They injected adenovirus containing the 5-HT1A sense sequence into the hypothalamus of SERT-deficient mice, partially restoring expression. SERT-/- mice responded to mild stress with increased adrenocorticotropin release, whereas 5-HT1A expression reduced this response. SERT-deficient mice also display decreased overall locomotor activity but increased exploratory behavior. Injection of 5-HT1A sense corrected the locomotion behavior but did not reduce the anxiety-related exploration. Injection of 5-HT1A antisense sequence into wild-type mice produced compatible results. The authors conclude that hypothalamic 5-HT1A receptors directly mediate hormonal stress response and defensive locomotion but not anxiety-like exploration.
Neurobiology of Disease
Rotenone and the Parkinsonian Fly
Hélène Coulom and Serge Birman
(see pages 10993-10998)
In this week's Journal, Coulom and Birman report on a fly model of sporadic Parkinson's disease (PD). Flies subjected to chronic sublethal exposure to the pesticide rotenone (a mitochondrial complex I inhibitor) displayed behavioral and neurological dysfunction similar to that seen with PD. A few days after rotenone was added to the fly chow, dose-dependent locomotor defects were apparent, as measured by their ability to ascend a 25 cm vertical plastic column (rock-climbing fly-style). The movement problems were accompanied by selective destruction of neurons in six clusters of dopaminergic cells. As in parkinsonian patients, l-dopa (3,4-dihydroxy-l-phenylalanine) improved the behavioral symptoms induced by rotenone but did not prevent dopaminergic neurodegeneration. Neuronal loss was rescued, however, by the antioxidant and free-radical scavenger melatonin (N-acetyl-5-methoxytryptamine). The rotenone model provides an interesting contrast to a fly PD model induced by overexpression of α-synuclein, a molecule that underlies hereditary cases of PD but is not present in the Drosophila genome.