A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane

Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry I_h, which contributes to neuronal excitability and signal transmission in the nervous system. Controlling the trafficking of HCN1 is an important aspect of its regulation, yet the details of this process are poorly understood. Here, we investigated how the C-terminus of HCN1 regulates trafficking by testing for its ability to redirect the localization of a non-targeted reporter in transgenic Xenopus laevis photoreceptors. We found that HCN1 contains an ER localization signal and through a series of deletion constructs, identified the responsible di-arginine ER retention signal. This signal is located in the intrinsically disordered region of the C-terminus of HCN1. To test the function of the ER retention signal in intact channels, we expressed wild type and mutant HCN1 in HEK293 cells and found this signal negatively regulates surface expression of HCN1. In summary, we report a new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway.     

Evolution of intrinsic disorder in eukaryotic proteins

Conformational flexibility conferred though regions of intrinsic structural disorder allows proteins to behave as dynamic molecules. While it is well-known that intrinsically disordered regions can undergo disorder-to-order transitions in real-time as part of their function, we also are beginning to learn more about the dynamics of disorder-to-order transitions along evolutionary time-scales. Intrinsically disordered regions endow proteins with functional promiscuity, which is further enhanced by the ability of some of these regions to undergo real-time disorder-to-order transitions. Disorder content affects gene retention after whole genome duplication, but it is not necessarily conserved. Altered patterns of disorder resulting from evolutionary disorder-to-order transitions indicate that disorder evolves to modify function through refining stability, regulation, and interactions. Here, we review the evolution of intrinsically disordered regions in eukaryotic proteins. We discuss the interplay between secondary structure and disorder on evolutionary time-scales, the importance of disorder for eukaryotic proteome expansion and functional divergence, and the evolutionary dynamics of disorder.     

Use of griseofulvin for the isolation of auxotrophic mutants ofRhodotorula sp.

Zusammenfassung Nach Vorbehandlung von Hefezellen mit Griseofulvin (selektive Eliminierung von Prototrophen) zu nachfolgender UV-Behandlung und Induktion von Mutanten, haben die bestrahlten Zellen der überlebendenRhodotorula-Population fünfmal mehr Auxotrophe als die Kontrollen ohne das Antibiotikum.     

The effect of oxymetholone on tissue replacement in the rabbit's ear

Résumé L'oxymétholone est un androgène synthétique qui stimule la régénération des tissus. Son action est plus efficace que celle du phényl-propionate-nandrolone, car elle produit le replacement des tissus dès les premiers stades de la régénération chez les mâles. De plus, elle a l'avantage de pouvoir être administrée oralement.

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The authors wish to thank MissM. Tydd for technical assistance and Syntex Pharmaceuticals Limited for the supply of oxymetholone.     

CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.     

Autumnal migration of Eared Grebes ( Podiceps nigricollis ) through southwestern Wyoming: a key to assessing the size of the North American population

In autumn the vast majority of the North American population of Eared Grebes ( Podiceps nigricollis ) congregates for several months at Great Salt Lake, Utah, and Mono Lake, California. Because the lakes are so large, it has not been possible to monitor grebe migration with sufficient accuracy to determine when peak numbers are reached. To clarify migration phenology, we analyzed data from 2 isolated wetland areas in southwestern Wyoming where grebes land en route between breeding areas in the interior and Great Salt Lake. Occasional birds, probably nonbreeders or failed breeders, begin moving southward as early as mid-June. Migration of postbreeding birds starts in late July, peaks in late August and September, and is largely completed by the end of October, with very small numbers arriving into November. The pattern of migration and number of birds encountered varied annually, but 95% of the migration was usually completed by 15 October. As a result, censuses at the major staging lake made on or after 15 October but before the grebes depart for wintering areas can be used to study trends in size of the North American population.