An E3 Ubiquitin Ligase, Really Interesting New Gene (RING) Finger 41, Is a Candidate Gene for Anxiety-Like Behavior and β-Carboline-Induced Seizures

Abstract

Identification of the genes underlying psychiatric illness remains a thorny problem. Previously, Quantitative Trait Loci (QTL) for anxiety-like behaviors and beta-carboline-induced seizure vulnerability have been mapped to the distal portion of mouse chromosome 10, with crosses of A/J and C57BL6 mice. An interval specific congenic strain for this chromosomal 10 region facilitated the genetic dissection of novelty-induced exploratory behaviors. By microarray studies, an unsuspected E3 ubiquitin ligase, Really Interesting New Gene (RING) Finger 41 (Rnf41) was differentially expressed in the region of interest, being upregulated in the hippocampi of B6 compared with A/J as well as congenic A.B6(chr10) versus A/J. By quantitative real-time polymerase chain reaction (qRT-PCR), Rnf41 expression levels were significantly increased 1.5- and 1.3-fold in the hippocampi of C57BL6/J and A.B6(chr10) mice compared with A/J mice, respectively. Protein levels of Rnf41 were increased in hippocampi of B6 mice compared with A/J mice across postnatal development with a 5.5-fold difference at P56. Yeast two-hybrid studies searching for Rnf41 binding partners in fetal hippocampus identified several potential targets. An interaction between Rnf41 and NogoA was validated by glutathionine-S-transferase-Rnf41 pulldown experiments. Re-analysis of a microarray database of human postmortem prefrontal cortex (Brodmann's Area 46/10) found that RNF41 messenger RNA expression levels were reduced significantly in patients with major depression and bipolar disorder compared with unaffected control subjects and confirmed by qRT-PCR. Overall, Rnf41 is nominated as a candidate gene for anxiety-like behaviors, depression, and vulnerability to seizures. The RNF41 and its binding partners suggest molecular pathways underlying behavior, highlighting a potential role for the ubiquitin proteasome system in psychiatric illness.