The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

Abstract

The tribbles (trbl) pseudokinases play important roles in signaling and physiology in multiple contexts, ranging from innate immunity to cancer, suggesting fundamental cellular functions for the trbls’ gene products. Despite expression of the trbl pseudokinases in the nervous systems of invertebrate and vertebrate animals, and evidence that they have a function within mouse and human dopamine neurons, there is no clear case for a function of a Trbl protein that influences behavior. Indeed, the first and only evidence for this type of function comes from Drosophila melanogaster, where a mutation of the single trbl gene was identified in a genetic screen for short-term memory mutant flies. The current study tested flies containing multiple trbl mutant alleles and potential transgenic rescue in both operant place memory and classical olfactory memory paradigms. Genetic complementation tests and transgenic rescue of memory phenotypes in both paradigms show that the D. melanogaster trbl pseudokinase is essential for proper memory formation. Expression analysis with a polyclonal antiserum against Trbl shows that the protein is expressed widely in the fly brain, with higher expression in the cellular rind than the neuropil. Rescue of the behavioral phenotype with transgenic expression indicates the trbl function can be localized to a subset of the nervous system. Thus, we provide the first compelling case for the function of a trbl pseudokinase in the regulation of behavior.

Control of Cell Growth and Proliferation by the Tribbles Pseudokinase: Lessons from Drosophila

“…Subsequent work showed that mammalian Trib1 and 2 bind and degrade C/EBP to promote T cell maturation, revealing the deep conservation of the interaction between Tribs and C/EBPs [ 10 , 76 ]. While multiple genetic screens conducted over the past 20 years have linked fly Trbl to tissue differentiation in the central nervous system [ 77 , 78 , 79 ], peripheral nervous system [ 80 ], musculature [ 81 ], testes [ 82 ], ovary [ 3 ], and eye [ 83 , 84 ], the specific Trbl targets active during these tissue differentiation events remain unknown.…”

“…Their demonstration that Trbl plays a critical role in the activation of quiescent neural stem cells during early larval development is intriguing in light of previous work done by Zars et al showing that trbl mutations result in adult behavior phenotypes, including sleep arrhythmias and short-term memory loss [ 78 , 79 ]. The Zars group showed that memory defects can be rescued by transgenic expression of Trbl in a subset of cells in the nervous system, making a compelling case that Trbl is critical for reorganization of neural circuitry necessary for subsequent adult behaviors.…”