Coordination of rhythmic locomotion depends upon a precisely balanced interplay between central and peripheral control mechanisms. Although poorly understood, peripheral proprioceptive mechanosensory input is thought to provide information about body position for moment-to-moment modifications of central mechanisms mediating rhythmic motor output. Pickpocket1 (PPK1) is a Drosophila subunit of the epithelial sodium channel (ENaC) family displaying limited expression in multiple dendritic (md) sensory neurons tiling the larval body wall and a small number of bipolar neurons in the upper brain. ppk1 null mutant larvae had normal external touch sensation and md neuron morphology but displayed striking alterations in crawling behavior. Loss of PPK1 function caused an increase in crawling speed and an unusual straight path with decreased stops and turns relative to wild-type. This enhanced locomotion resulted from sustained peristaltic contraction wave cycling at higher frequency with a significant decrease in pause period between contraction cycles. The mutant phenotype was rescued by a wild-type PPK1 transgene and duplicated by expressing a ppk1RNAi transgene or a dominant-negative PPK1 isoform. These results demonstrate that the PPK1 channel plays an essential role in controlling rhythmic locomotion and provide a powerful genetic model system for further analysis of central and peripheral control mechanisms and their role in movement disorders.
Growth of multicellular organisms proceeds through a series of precisely timed developmental events requiring coordination between gene expression, behavioral changes, and environmental conditions. In Drosophila melanogaster larvae, the essential midthird instar transition from foraging (feeding) to wandering (non-feeding) behavior occurs prior to pupariation and metamorphosis. The timing of this key transition is coordinated with larval growth and size, but physiological mechanisms regulating this process are poorly understood. Results presented here show that Drosophila larvae associate specific environmental conditions, such as temperature, with food in order to enact appropriate foraging strategies. The transition from foraging to wandering behavior is associated with a striking reversal in the behavioral responses to food-associated stimuli that begins early in the third instar, well before food exit. Genetic manipulations disrupting expression of the Degenerin/Epithelial Sodium Channel subunit, Pickpocket1(PPK1) or function of PPK1 peripheral sensory neurons caused defects in the timing of these behavioral transitions. Transient inactivation experiments demonstrated that sensory input from PPK1 neurons is required during a critical period early in the third instar to influence this developmental transition. Results demonstrate a key role for the PPK1 sensory neurons in regulation of important behavioral transitions associated with developmental progression of larvae from foraging to wandering stage.
Background The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between LH and LN was comprehensively studied. Methods and Results Multi-dimensional data were obtained including genotypes of 1536 SNPs, 23 physiological traits and more than 150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression QTL were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with pQTL loci. We found an eQTL hotspot on rat chromosome 17 that is causally associated with multiple MetS-related traits, and found RGD1562963, a gene regulated in cis by this eQTL hotspot, as the most likely eQTL driver gene directly affected by genetic variation between LH and LN rats. Conclusions Our study sheds light on the intricate pathogenesis of MetS and demonstrates that systems biology with high-throughput sequencing is a powerful method to study the etiology of complex genetic diseases.
Palygin OA, Pettus JM, Shibata EF. Regulation of caveolar cardiac sodium current by a single Gs␣ histidine residue. Am J Physiol Heart Circ Physiol 294: H1693-H1699, 2008. First published February 8, 2008 doi:10.1152/ajpheart.01337.2007.-Cardiac sodium channels (voltage-gated Na ϩ channel subunit 1.5) reside in both the plasmalemma and membrane invaginations called caveolae. Opening of the caveolar neck permits resident channels to become functional. In cardiac myocytes, caveolar opening can be stimulated by applying -receptor agonists, which initiates an interaction between the stimulatory G protein subunit-␣ (Gs␣) and caveolin-3. This study shows that, in adult rat ventricular myocytes, a functional Gs␣-caveolin-3 interaction occurs, even in the absence of the caveolin-binding sequence motif of Gs␣. Consistent with previous data, whole cell experiments conducted in the presence of intracellular PKA inhibitor stimulation with -receptor agonists increased the sodium current (INa) by 35.9 Ϯ 8.6% (P Ͻ 0.05), and this increase was mimicked by application of Gs␣ protein. Inclusion of anti-caveolin-3 antibody abolished this effect. These findings suggest that Gs␣ and caveolin-3 are components of a PKA-independent pathway that leads to the enhancement of INa. In this study, alanine scanning mutagenesis of Gs␣ (40THR42), in conjunction with voltage-clamp studies, demonstrated that the histidine residue at position 41 of Gs␣ (H41) is a critical residue for the functional increase of INa. Protein interaction assays suggest that Gs␣FL (full length) binds to caveolin-3, but the enhancement of INa is observed only in the presence of Gs␣ H41. We conclude that Gs␣ H41 is a critical residue in the regulation of the increase in INa in ventricular myocytes.
The ovarian tumor gene is required during both early and late stages of oogenesis. Mutations produce a range of phenotypes, including agametic ovarioles, tumorous egg chambers, and late stage oogenic arrest. We demonstrate that each of these phenotypes is associated with specific aberrations in actin distribution. In the earliest case, ovarian tumor mutations cause actin filaments to accumulate ectopically in the fusome. This correlates with abnormal fusome morphology and arrested germ cell development in the germaria. Similarly, ovarian tumor function is required for the localization of actin that is essential for the maturation of ring canals. This defect gives rise to tumorous egg chambers in which germ cell numbers and morphology are profoundly aberrant. We also confirm that ovarian tumor is required for the formation of the nurse cell cytoplasmic actin array that is essential for the nonspecific transport of cytoplasmic contents to the oocyte during late oogenesis. Our data suggest that at this stage ovarian tumor controls the site where actin filaments initiate. Taken together, these studies suggest that the diverse ovarian tumor mutant phenotypes derive from the mislocalization of actin filaments, indicating a role for this gene in organizing the female germline cytoskeleton, and that the misregulation of actin can have profound effects on germ cell division and differentiation.
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