Central Regulation of Locomotor Behavior of <i>Drosophila melanogaster</i> Depends on a CASK Isoform Containing CaMK-Like and L27 Domains

Slawson, Justin B.; Kuklin, Elena A.; Ejima, Aki; Mukherjee, Konark; Ostrovsky, Lilly; Griffith, Leslie C.

doi:10.1534/genetics.110.123406

Cited by 41 publications

(88 citation statements)

References 51 publications

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“…These were CASK, Dys and Frq2; Dys and Frq2 were also were represted by multiple GO terms (see above). CASK has been shown to regulate neurotransmitter release (Zordan et al 2005) and affect locomotor activity (Sun et al 2009;Slawson et al 2011). cv-c (also represented by multiple GO terms, see above) was associated with both GSEI and aggression of flies from the socially isolated environment.…”

Section: Insights About the Molecular Genetic Basis Of Natural Variatmentioning

confidence: 99%

Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior

et al. 2017

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Human psychiatric disorders such as schizophrenia, bipolar disorder and attention-deficit/hyper-activity disorder often include adverse behaviors including increased aggressiveness. Individuals with psychiatric disorders often exhibit social withdrawal, which can further increase the probability of conducting a violent act. Here, we used the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP) to investigate the genetic basis of variation in male aggressive behavior for flies reared in a socialized and socially isolated environment. We identified genetic variation for aggressive behavior, as well as significant genotype by social environmental interaction (GSEI); i.e., variation among DGRP genotypes in the degree to which social isolation affected aggression. We performed genome-wide association (GWA) analyses to identify genetic variants associated with aggression within each environment. We used genomic prediction to partition genetic variants into gene ontology (GO) terms and constituent genes, and identified GO terms and genes with high prediction accuracies in both social environments and for GSEI. The top predictive GO terms significantly increased the proportion of variance explained, compared to prediction models based on all segregating variants. We performed genomic prediction across environments, and identified genes in common between the social environments which turned to be enriched for genome-wide associated variants.A large proportion of the associated genes have previously been associated with aggressive behavior in Drosophila and mice.Further, many of these genes have human orthologs that have been associated with neurological disorders, indicating partially shared genetic mechanisms underlying aggression in animal models and human psychiatric disorders.

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Section: Insights About the Molecular Genetic Basis Of Natural Variatmentioning

confidence: 99%

Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior

et al. 2017

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“…There is no known orthologue of MPP1 in invertebrates. The CASK gene in invertebrates, however, is known to produce a protein with an alternative N-terminus (CASK-α in Drosophila and Lin-2b in nematodes) [15] (Figure 2A). In Drosophila, this alternative protein (CASK-α; Figure 2A) starts with a signature palmitoylation sequence and may represent an MPP1-like protein.…”

Section: Gene Sizementioning

confidence: 99%

“…The broken line represents the longest CASK orthologue gene represented in invertebrates. not seem to arise from a defect in motor neurons or premotor neuropil, and no obvious structural or developmental abnormalities are observed [15]. These distinct and unrelated phenotypes of CASK deletion in different animal models are difficult to reconcile and underscore a clear need to understand the evolution of the CASK gene.…”

Section: Introductionmentioning

confidence: 99%

Structural constraints and functional divergences in CASK evolution

LaConte

Mukherjee

2013

Biochemical Society Transactions

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CASK (Ca2+/calmodulin-activated serine kinase) is a synaptic protein that interacts with the cytosolic tail of adhesion molecules such as neurexins, syncam and syndecans. It belongs to the MAGUK (membrane-associated guanylate kinase) family of scaffolding proteins which are known to decorate cell-cell junctions. CASK is an essential gene in mammals, critical for neurodevelopment. Mutations in the CASK gene in humans result in phenotypes that range from intellectual disability to lethality. Despite its importance, CASK has a single genetic isoform located in the short arm of the X chromosome near an evolutionary breakpoint. Surprisingly, CASK is a non-essential gene in invertebrates and displays functional divergence. In the present article, we describe the phylogenetic differences in existing CASK orthologues. The CASK gene has undergone a huge expansion in size (~55-fold). Almost all of this expansion is a direct result of an increase in the size of the introns. The coding region of CASK orthologues, and hence the protein, exhibit a high degree of evolutionary conservation. Within the protein, domain arrangement is completely conserved and substitution rates are higher in the connecting loop regions [L27 (Lin2, Lin7)] than within the domain. Our analyses of single residue substitutions and genotype-phenotype relationships suggest that, other than intronic expansion, the dramatic functional changes of CASK are driven by subtle (non-radical) primary structure changes within the CASK protein and concomitant changes in its protein interactors.

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“…2 Flies were transferred to fresh food vials every 3 to 4 days. Only male flies were used in the current study, consistent with use of males in the original longevity study of mth mutants, as well as several other prior studies of Drosophila behavior (Lin et al 1998;Petrosyan et al 2007;Bland et al 2009;Slawson et al 2011). A total of 158 flies (81 mth and 77 controls) were individually tethered and tested in the flight-duration experiment, and 173 different flies (97 mth and 76 controls) in the locomotion (exploratory walking) experiment.…”

Section: Fly Stocksmentioning

confidence: 99%

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

Petrosyan

Gonçalves

Hsieh

et al. 2013

AGE

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Methuselah (mth) is a chromosome 3 Drosophila mutant with an increased lifespan. A large number of studies have investigated the genetic, molecular, and biochemical mechanisms of the mth gene. Much less is known about the effects of mth on preservation of sensorimotor abilities throughout Drosophila's lifespan, particularly in late life. The current study investigated functional senescence in mth and its parental-control line (w1118) in two experiments that measured age-dependent changes in flight functions and locomotor activity. In experiment 1, a total of 158 flies (81 mth and 77 controls) with an age range from 10 to 70 days were individually tethered under an infrared laser-sensor system that allowed monitoring of flight duration during phototaxic flight. We found that mth has a statistically significant advantage in maintaining continuous flight over control flies at age 10 days, but not during middle and late life. At age 70 days, the trend reversed and parental control flies had a small but significant advantage, suggesting an interaction between age and genotype in the ability to sustain flight. In experiment 2, a total of 173 different flies (97 mth and 76 controls) with an age range from 50 to 76 days were individually placed in a large well-lit arena (60×45 cm) and their locomotor activity quantified as the distance walked in a 1-min period. Results showed that mth flies had lower levels of locomotor activity relative to controls at ages 50 and 60 days. These levels converged for the two genotypes at the oldest ages tested. Findings show markedly different patterns of functional decline for the mth line relative to those previously reported for other life-extended genotypes, suggesting that different life-extending genes have dissimilar effects on preservation of sensory and motor abilities throughout an organism's lifespan.

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Central Regulation of Locomotor Behavior of Drosophila melanogaster Depends on a CASK Isoform Containing CaMK-Like and L27 Domains

Cited by 41 publications

References 51 publications

Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior

Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior

Structural constraints and functional divergences in CASK evolution

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

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