Ret Signaling and Lipid Rafts
Brian A. Pierchala, Jeffrey Milbrandt, and Eugene M. Johnson Jr
(see pages 2777–2787)
Pierchala et al. this week followed the plight of the receptor tyrosine kinase (RTK) Ret after its activation. Ret is activated by a complex consisting of a member of the glial cell line-derived neurotrophic factor (GDNF) family and a glycerophosphatidylinositol (GPI)-linked coreceptor. The GPI linkage results in recruitment of Ret into lipid rafts, where its activity is maximal. The authors report that, once activated, Ret disappeared from rat sympathetic neurons over several hours. Some Ret was monoubiquitinated and targeted to the lysosome, but a more substantial fraction was polyubiquitinated and thus sent to proteasomes for degradation. Ret degradation effectively terminated the GDNF-mediated signal. When the authors disrupted lipid rafts, GDNF-mediated neuronal survival was severely diminished, an effect that was reversed by inhibition of proteasomal degradation. Thus, lipid rafts serve to sequester activated Ret and extend its activity.
REST in Xenopus Development
Patricio Olguín, Pablo Oteíza, Eduardo Gamboa, José Luis Gómez-Skármeta, and Manuel Kukuljan
(see pages 2820–2829)
The transcriptional repressor RE-1 silencer of transcription/neural restrictive silencer factor (REST/NRSF) is best known for its role in silencing neural genes in non-neuronal cells. However, it now appears that REST has more widespread actions in organogenesis and development. This week, Olguín et al. considered its role in vivo during Xenopus laevis development. In embryos, the authors expressed a glucocorticoid-inducible dominant-negative construct (dnXREST) that bound to the DNA of target genes but not corepressor proteins. In a second approach, REST translation was blocked by a morpholino antisense oligonucleotide (MoXREST). Activation of dnXREST resulted in decreased expression of several neuronal genes at the late blastula stage. But perhaps more importantly, XREST was required for neuroectodermal patterning during gastrulation, pointing to a broader developmental role in the acquisition of specific ectodermal cell fates. The authors suggest that, at least in part, the impairments of REST function may result from reduced BMP signaling.
The Organization of the Dorsal Premotor Cortex
Céline Amiez, Penelope Kostopoulos, Anne-Sophie Champod, and Michael Petrides
(see pages 2724–2731)
Functional magnetic resonance imaging (fMRI) studies have suggested that the dorsal premotor cortex is the site of visuomotor hand conditional activity, as well as the frontal eye field (FEF). This week, Amiez et al. addressed whether these functions actually reside in the same location at the intersection of the superior frontal sulcus (SFS) and the superior precentral sulcus (SPS). The authors tackled the issue in humans with a subject-by-subject investigation, using fMRI, of the area. Subjects were given tasks to activate both conditional hand movements in which they pushed a specific button corresponding to each of four colors that appeared on a screen and saccadic eye movements by following the movements of a black dot onscreen. The authors report that the human SPS actually consists of two sulci, which they term the ventral and dorsal branches. As in monkey, the visuomotor hand locus was located immediately dorsocaudal to the FEF.
Neurobiology of Disease
Histone Deacetylases and Huntingtin Toxicity in C. elegans
Emily A. Bates, Martin Victor, Adriana K. Jones, Yang Shi, and Anne C. Hart
(see pages 2830–2838)
This week, Bates et al. explore the proposed connection between trinucleotide repeat diseases and dysregulation of gene transcription. The authors used transgenic Caenorhabditis elegans that expressed an expanded polyglutamine fragment of human huntingtin (Htn-Q150) in a subset of sensory neurons. Neurodegeneration in the sensory cells was monitored by loss of uptake of a lipophilic fluorescent dye. Htn-Q150-induced neurodegeneration was enhanced if the C. elegans homolog of CREB-binding protein, cbp-1, was reduced, or if the CREB homolog crh-1 was deleted. If polyglutamine fragments interfere with the histone acetyltransferase activity of CBP, inhibition of deacetylase should be neuroprotective. In fact, the histone deacetylase (HDAC) inhibitor trichostatin A did reduce Htn-Q150 neurodegeneration, but knockdown of individual HDACs provided a more complex result. Generally, loss of individual C. elegans HDACs enhanced toxicity, but neurons actually benefited from knockdown of had-3. HAD-3 and CRH-1 apparently regulate transcript genes with opposing effects on Htn-Q150-induced neurodegeneration. ⇓