Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation.

Dosage compensation is an essential process that equalizes transcript levels of X-linked genes between sexes by forming a domain of coordinated gene expression. Throughout the evolution of Diptera, many different X-chromosomes acquired the ability to be dosage compensated. Once each newly evolved X-chromosome is targeted for dosage compensation in XY males, its active genes are upregulated two-fold to equalize gene expression with XX females. In Drosophila melanogaster, the CLAMP zinc finger protein links the dosage compensation complex to the X-chromosome. However, the mechanism for X-chromosome identification has remained unknown. Here, we combine biochemical, genomic and evolutionary approaches to reveal that expansion of GA-dinucleotide repeats likely accumulated on the X-chromosome over evolutionary time to increase the density of CLAMP binding sites, thereby driving the evolution of dosage compensation. Overall, we present new insight into how subtle changes in genomic architecture, such as expansions of a simple sequence repeat, promote the evolution of coordinated gene expression.

Neuroendocrine gene expression coupling of interoceptive bacterial food cues to foraging behavior of C. elegans.

Animal internal state is modulated by nutrient intake, resulting in behavioral responses to changing food conditions. The neural mechanisms by which internal states are generated and maintained are not well understood. Here, we show that in the nematode Caenorhabditis elegans, distinct cues from bacterial food - interoceptive signals from the ingestion of bacteria and gustatory molecules sensed from nearby bacteria - act antagonistically on the expression of the neuroendocrine TGF-beta ligand DAF-7 from the ASJ pair of sensory neurons to modulate foraging behavior. A positive-feedback loop dependent on the expression of daf-7 from the ASJ neurons acts to promote transitions between roaming and dwelling foraging states and influence the persistence of roaming states. SCD-2, the C. elegans ortholog of mammalian anaplastic lymphoma kinase (ALK), which has been implicated in the central control of metabolism of mammals, functions in the AIA interneurons to regulate foraging behavior and cell-non-autonomously control the expression of DAF-7 from the ASJ neurons. Our data establish how a dynamic neuroendocrine daf-7 expression feedback loop regulated by SCD-2 functions to couple sensing and ingestion of bacterial food to foraging behavior. We further suggest that this neuroendocrine feedback loop underlies previously characterized exploratory behaviors in C. elegans. Our data suggest that the expression of daf-7 from the ASJ neurons contributes to and is correlated with an internal state of 'unmet need' that regulates exploratory foraging behavior in response to bacterial cues in diverse physiological contexts.

Genetic variants that modify neuroendocrine gene expression and foraging behavior of C. elegans.

The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. In Caenorhabditis elegans, the neuroendocrine transforming growth factor-ß ligand, DAF-7, regulates diverse behavioral responses to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons. We identified common genetic variants in gap-2, encoding a Ras guanosine triphosphatase (GTPase)-activating protein homologous to mammalian synaptic Ras GTPase-activating protein, which modify daf-7 expression cell nonautonomously and promote exploratory foraging behavior in a partially DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.

Neuroendocrine Gene Expression Coupling of Interoceptive Bacterial Food Cues to Foraging Behavior of C. elegans.

Animal internal state is modulated by nutrient intake, resulting in behavioral responses to changing food conditions. The neural mechanisms by which internal states are generated and maintained are not well understood. Here, we show that in the nematode Caenorhabditis elegans, distinct cues from bacterial food - interoceptive signals from the ingestion of bacteria and gustatory molecules sensed from nearby bacteria - act antagonistically on the expression of the neuroendocrine TGF-beta ligand DAF-7 from the ASJ pair of sensory neurons to modulate foraging behavior. A positive-feedback loop dependent on the expression of daf-7 from the ASJ neurons acts to promote transitions between roaming and dwelling foraging states and influence the persistence of roaming states. SCD-2, the C. elegans ortholog of mammalian Anaplastic Lymphoma Kinase (ALK), which has been implicated in the central control of metabolism of mammals, functions in the AIA interneurons to regulate foraging behavior and cell-non-autonomously control the expression of DAF-7 from the ASJ neurons. Our data establish how a dynamic neuroendocrine daf-7 expression feedback loop regulated by SCD-2 functions to couple sensing and ingestion of bacterial food to foraging behavior. We further suggest that this neuroendocrine feedback loop underlies previously characterized exploratory behaviors in C. elegans. Our data suggest that the expression of daf-7 from the ASJ neurons contributes to and is correlated with an internal state of "unmet need" that regulates exploratory foraging behavior in response to bacterial cues in diverse physiological contexts.

Genetic Variants That Modify the Neuroendocrine Regulation of Foraging Behavior in C. elegans.

The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. The neuroendocrine TGF-beta ligand, DAF-7, regulates diverse behavioral responses of Caenorhabditis elegans to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons and identified common variants in gap-2, encoding a GTPase-Activating Protein homologous to mammalian SynGAP proteins, which modify daf-7 expression cell-non-autonomously and promote exploratory foraging behavior in a DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.