LRRTM1 underlies synaptic convergence in visual thalamus.

It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.

Arf6 and the 5'phosphatase of synaptojanin 1 regulate autophagy in cone photoreceptors.

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1-deficient zebrafish mutant, nrc(a14) . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrc(a14) cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrc(a14) cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type.

Arf6 and the 5'phosphatase of Synaptojanin 1 regulate autophagy in cone photoreceptors.

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated Synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1-deficient zebrafish mutant, nrca14 . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate due to a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5' phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type.

Phase II trial of thalidomide and daily oral dexamethasone for treatment of hormone refractory prostate cancer progressing after chemotherapy.

BACKGROUND: Responses to monotherapy corticosteroid or thalidomide have been described in prostate cancer, in chemotherapy naïve subjects. METHODS: A total of 39 men with hormone refractory, metastatic prostate cancer who had progression during or after at least 1 conventional cytotoxic drug were treated on a single-arm Phase II trial with dexamethasone, 0.75 mg twice a day plus thalidomide, 100-400 mg/day. RESULTS: Best-observed responses included >50% prostate-specific antigen (PSA) reduction with no radiologic progression: 10 of 39 (26%; 95% confidence interval 13% to 42%). An additional 14 of 39 had decreased PSA but then with radiologic or other progression by 12 weeks. Median progression-free survival was 84 days. Toxicity appeared treatable; there were 5 nonfatal thromboses. There was 1 subject who had complete PSA and radiologic response; 4 responders tolerated treatment without progression for more than 1 year. CONCLUSIONS: PSA responses were frequent. Mostly, these were not durable, but some lasted more than a year. Further investigation on determinants of response durability for these or related compounds should be considered. The response rate of the present data does not support Phase III testing of this regimen for this population.