Trib3 Is Developmentally and Nutritionally Regulated in the Brain but Is Dispensable for Spatial Memory, Fear Conditioning and Sensing of Amino Acid-Imbalanced Diet

Abstract

Tribbles homolog 3 (TRIB3) is a mammalian pseudokinase that is induced in neuronal cell cultures in response to cell death-inducing stresses, including neurotrophic factor deprivation. TRIB3 is an inhibitor of activating transcription factor 4 (ATF4), the central transcriptional regulator in the eukaryotic translation initiation factor 2α (eIF2α) phosphorylation pathway that is involved in the cellular stress response and behavioral processes. In this article, we study the expression of Trib3 in the mouse brain, characterize the brain morphology of mice with a genetic ablation of Trib3 and investigate whether Trib3 deficiency alters eIF2α-dependent cognitive abilities. Our data show that the consumption of a leucine-deficient diet induces Trib3 expression in the anterior piriform cortex, the brain region responsible for detecting essential amino acid intake imbalance. However, the aversive response to leucine-devoid diet does not differ in Trib3 knockout and wild type mice. Trib3 deletion also does not affect long-term spatial memory and reversal learning in the Morris water maze and auditory or contextual fear conditioning. During embryonic development, Trib3 expression increases in the brain and persists in the early postnatal stadium. Neuroanatomical characterization of mice lacking Trib3 revealed enlarged lateral ventricles. Thus, although the absence of Trib3 does not alter the eIF2α pathway-dependent cognitive functions of several areas of the brain, including the hippocampus, amygdala and anterior piriform cortex, Trib3 may serve a role in other central nervous system processes and molecular pathways.

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

“…Interestingly, a TRIB3-regulated AKT-FOXO transcriptional network also operates in human neurons [27], where TRIB3 expression levels are inversely correlated with the Parkinson's disease-associated ubiquitin E3 ligase PARKIN [31]. Indeed, TRIB3, but not TRIB1 or TRIB2, mRNA expression is upregulated in the developing murine brain [32] and TRIB3 immunostaining is markedly increased in sections of substantia nigra from Parkinson's disease brains [31]. The relatively mild cognitive and memory brain phenotypes observed in a C57BL/6 TRIB3-deficient mouse model [31] support the notion that normalizing pathological increases in TRIB3 levels in neurodegenerative disease might be an interesting new medical strategy.…”

The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

“…Although the trbl pseudokinase in Drosophila , and the vertebrate trbl 1–3, are expressed in the brain (Figure 3) (Aime et al, 2015; Fisher et al, 2012; Ord et al, 2014), the results here provide the first definitive evidence for the function of this protein in regulating behavior. We show that the trbl gene is critical for normal memory formation.…”

“…Mouse and man have three, named trbl 1, 2, and 3 (Boudeau, Miranda-Saavedra, Barton, & Alessi, 2006; Eyers et al, 2016). There is wide-spread expression of the three mammalian trbl products in brain and the D. melanogaster trbl gene is expressed in the developing nervous system (Aime, Sun, Zareen, Rao, Berman, Volpicelli-Daley, Bernd, Crary, Levy, & Greene, 2015; Fisher, Li, Hammonds, Brown, Pfeiffer, Weiszmann, MacArthur, Thomas, Stamatoyannopoulos, Eisen, Bickel, Biggin, & Celniker, 2012; Ord, Innos, Lillevali, Tekko, Sutt, Ord, Koks, Vasar, & Ord, 2014). Nevertheless, there is little known about how trbl influences brain function.…”

“…The vertebrate trbl 3 has been implicated in Parkinson’s disease as a cell death promoter in dopaminergic neurons (Aime et al, 2015). However, knock-out of trbl 3 in the mouse has no effect on feeding behavior, or learning and memory in three different paradigms (Ord et al, 2014). Behavioral tests on trbl 1 or 2 have not been reported (Lin, Yang-Yen, Lien, Liao, Huang, Lin, Li, & Yen, 2016; Satoh, Kidoya, Naito, Yamamoto, Takemura, Nakagawa, Yoshioka, Morii, Takakura, Takeuchi, & Akira, 2013).…”

TRIB3 enhances cell viability during glucose deprivation in HEK293-derived cells by upregulating IGFBP2, a novel nutrient deficiency survival factor

“…34 Since TRIB3 augments IGFBP2 expression in glucose-starved cells, the data indicate that IGFBP2 contributes to 35 the attenuation of cell death by TRIB3. These results implicate TRIB3 and IGFBP2, both of which are known to 36 be overexpressed in several types of cancers, as pro-survival modulators of cell viability in nutrient-deficient 37 microenvironments. 38 © 2015 Published by Elsevier B.V. Glucose deprivation is a cell death-inducing condition that occurs 45 during diseases such as cerebral and myocardial infarctions, due to a 46 blockage of blood flow, and in the central regions of solid tumors, due 47 to insufficient vascularization.…”