Phenotypic Analysis of LUMAN/CREB3 Deficient Mice: a Novel Role of LUMAN in the Regulation of Emotion, Locomotor Activity, Maternal Response, and Energy Balance

Abstract

LUMAN is a transcription factor involved in the regulation of endoplasmic reticulum stress and viral infection. The expression sites of LUMAN in tissues and organs and its biological function haven’t been explored. We aimed to investigate the biological function of LUMAN in the relevant tissue and the underlying mechanism in this study. We found that LUMAN was abundantly expressed in the nuclei of neurons in many regions of the central nervous system including the forebrain, the midbrain, and the cerebellum. Particularly, LUMAN-positive neurons aggregated in four areas where the cell bodies of the principle neurons are located: the mitral cell layer of the olfactory bulb, the stratum pyramidale of the hippocampus, the stratum granulosum of the dentate gyrus region of the hippocampus, and the Purkinje layer of the cerebellum. We characterized at least two unknown phenotypes of Luman-/- mice in body weight and animal behaviour respectively. In conspicuous contrast with its wild-type littermates, both male and female Luman-/- mice were spontaneous lean without any substantial body weight gain over time. Pups born to Luman-/- dams all died within two days after birth. Obvious lactation and olfaction defects were excluded from the possible causes. Video monitoring revealed impulsive and hyperactive activity of Luman-/- dams that might have directly caused the deaths of the pups. Virgin female Luman-/- mice displayed reduction of anxiety-like behaviour and hyperactive behavior. Additionally, the expression of anti-apoptotic genes (Bcl-2 and Bcl-xl) was repressed while the expression of pro-apoptotic genes (Bax, Puma, Noxa, and Caspase 3) was elevated in Luman-/- mouse embryonic fibroblasts as compared to Luman+/+ mouse embryonic fibroblasts. We propose that LUMAN plays an important role in the regulation of emotion, associated locomotor activity, and energy balance in the central nervous system. Our data provides new insights into understanding the biological function of the Luman gene. Luman gene knockout mice provide a potential animal model for studying the underlying molecular mechanisms and the therapeutic treatments for neuropsychiatric or obesity related disorders.