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Nutrient acquisition and energy storage are critical parts of achieving metabolic homeostasis. The foraging gene in Drosophila melanogaster has previously been implicated in multiple feeding-related and metabolic traits. Before foraging's functions can be further dissected, we need a precise genetic null mutant to definitively map its amorphic phenotypes. We used homologous recombination to precisely delete foraging, generating the for(0) null allele, and used recombineering to reintegrate a full copy of the gene, generating the {for(BAC)} rescue allele. We show that a total loss of foraging expression in larvae results in reduced larval path length and food intake behavior, while conversely showing an increase in triglyceride levels. Furthermore, varying foraging gene dosage demonstrates a linear dose-response on these phenotypes in relation to foraging gene expression levels. These experiments have unequivocally proven a causal, dose-dependent relationship between the foraging gene and its pleiotropic influence on these feeding-related traits. Our analysis of foraging's transcription start sites, termination sites, and splicing patterns using rapid amplification of cDNA ends (RACE) and full-length cDNA sequencing, revealed four independent promoters, pr1-4, that produce 21 transcripts with nine distinct open reading frames (ORFs). The use of alternative promoters and alternative splicing at the foraging locus creates diversity and flexibility in the regulation of gene expression, and ultimately function. Future studies will exploit these genetic tools to precisely dissect the isoform- and tissue-specific requirements of foraging's functions and shed light on the genetic control of feeding-related traits involved in energy homeostasis.

Original publication

DOI

10.1534/genetics.116.197939

Type

Journal article

Journal

Genetics

Publication Date

02/2017

Volume

205

Pages

761 - 773

Keywords

behavior, fat, foraging gene, larva, null mutant, Animals, Cyclic GMP-Dependent Protein Kinases, Drosophila Proteins, Drosophila melanogaster, Feeding Behavior, Gene Dosage, Genetic Pleiotropy, Phenotype, Promoter Regions, Genetic, RNA Splicing, Triglycerides