Expression and glucocorticoid-dependent regulation of the stress-inducible protein DRR1 in the mouse adult brain

Mercè Masana,Theo Rein,Mathias V Schmidt,Marianne B Müller,Anja Kretzschmar,Sara Santarelli,Giulia Treccani,Sören Westerholz,Claudia Liebl,Carine Dournes,Maurizio Popoli

doi:10.1007/s00429-018-1737-7

Abstract

Identifying molecular targets that are able to buffer the consequences of stress and therefore restore brain homeostasis is essential to develop treatments for stress-related disorders. Down-regulated in renal cell carcinoma 1 (DRR1) is a unique stress-induced protein in the brain and has been recently proposed to modulate stress resilience. Interestingly, DRR1 shows a prominent expression in the limbic system of the adult mouse. Here, we analyzed the neuroanatomical and cellular expression patterns of DRR1 in the adult mouse brain using in situ hybridization, immunofluorescence and Western blot. Abundant expression of DRR1 mRNA and protein was confirmed in the adult mouse brain with pronounced differences between distinct brain regions. The strongest DRR1 signal was detected in the neocortex, the CA3 region of the hippocampus, the lateral septum and the cerebellum. DRR1 was also present in circumventricular organs and its connecting regions. Additionally, DRR1 was present in non-neuronal tissues like the choroid plexus and ependyma. Within cells, DRR1 protein was distributed in a punctate pattern in several subcellular compartments including cytosol, nucleus as well as some pre- and postsynaptic specializations. Glucocorticoid receptor activation (dexamethasone 10 mg/kg s.c.) induced DRR1 expression throughout the brain, with particularly strong induction in white matter and fiber tracts and in membrane-rich structures. This specific expression pattern and stress modulation of DRR1 point to a role of DRR1 in regulating how cells sense and integrate signals from the environment and thus in restoring brain homeostasis after stressful challenges.

Highlights

Stress induces a plethora of molecular changes in the brain aimed at facilitating individual adaptation to new environmental demands
From anterior to posterior relative to bregma, the strongest Down-regulated in renal cell carcinoma 1 (DRR1) mRNA expression was detected in the posterior part of the lateral septum; the subfornical organ; the cell bodies of the pyramidal CA3 region of the hippocampus, the CA3a and initial part of CA3b subfield; and cells ensheathing the stalk of the habenular commissure and the Purkinje cell layer of the cerebellum
We provide a comprehensive description of the neuroanatomical expression of DRR1 in the adult mouse brain and its regulation by glucocorticoids

Summary

Introduction

Stress induces a plethora of molecular changes in the brain aimed at facilitating individual adaptation to new environmental demands. The stress-inducible gene down-regulated in renal cell carcinoma 1 (DRR1, known as TU3A and Fam107A) was initially identified as a putative tumor suppressor gene in renal cell carcinoma (Yamato et al 2000; Wang et al 2000), as unique gene increased in both psychiatric and neurodegenerative disorders (Shao and Vawter 2008; Li et al 2014; Shin et al 2016) and recently pointed as a novel molecular player promoting stress resilience (Masana et al 2014, 2015; van der Kooij et al 2016), supporting the involvement of DRR1 in modulating neuronal function under pathophysiological conditions. Virus-induced overexpression of DRR1 in these brain regions improves cognitive performance (Schmidt et al 2011) and increases social behavior (Masana et al 2014), suggesting that DRR1 facilitate specific behaviors which might be protective against some of the deleterious consequences of stress exposure

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