Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders

Abstract

BackgroundWe have previously identified BRINP (BMP/RA-inducible neural-specific protein-1, 2, 3) family genes that possess the ability to suppress cell cycle progression in neural stem cells. Of the three family members, BRINP1 is the most highly expressed in various brain regions, including the hippocampus, in adult mice and its expression in dentate gyrus (DG) is markedly induced by neural activity. In the present study, we generated BRINP1-deficient (KO) mice to clarify the physiological functions of BRINP1 in the nervous system.ResultsNeurogenesis in the subgranular zone of dentate gyrus was increased in BRINP1-KO mice creating a more immature neuronal population in granule cell layer. The number of parvalbumin expressing interneuron in hippocampal CA1 subregion was also increased in BRINP1-KO mice. Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention–deficit/hyperactivity disorder (ADHD).ConclusionsAbsence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry. Abnormal behaviors comparable to those of human psychiatric disorders such as hyperactivity and poor social behavior were observed in BRINP1-KO mice. These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.

Development of the Cellular Immune System of Drosophila Requires the Membrane Attack Complex/Perforin-Like Protein Torso-Like

“…A candidate growth factor signaling pathway is the platelet-derived growth factor and vascular endothelial growth factor receptor (PVR) pathway, which plays a crucial role in Drosophila hemocyte survival and differentiation (Heino et al 2001;Munier et al 2002;Bruckner et al 2004). We further note that a developmental role has been ascribed for a number of neural MACPF proteins in mammals (Zheng et al 1996;Adams et al 2002;Kobayashi et al 2014). Thus, given our findings in Drosophila, it is possible that a role for MACPF proteins in mammalian immune cell development has been overlooked.…”

“…However, it is important to note that certain MACPF proteins perform roles outside immunity or pathogenicity. For example a group of MACPF proteins in mammals is important for brain development (Zheng et al 1996;Adams et al 2002;Kobayashi et al 2014), and the subject of this study, Torso-like (Tsl), is crucial for embryonic and larval development in Drosophila (Stevens et al 1990;Martin et al 1994;Johnson et al 2013). It is currently unclear whether pore formation is central to the function of these molecules.…”

The impact of clinical heterogeneity in schizophrenia on genomic analyses

“…The other flanking gene, deleted in bladder cancer 1 ( DBC1 , formerly BRINP1 ), suppresses cell cycle progression in neural stem cells and is highly expressed in the brain (Kawano et al, 2004). The absence of BRINP1 in mice causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry, resulting in hyperactivity and poor social behavior (Kobayashi et al, 2014). Furthermore, linkage to a nearby marker in the 9q33.1 region was also observed for genetic modifiers of the clinical course of SZ (Fanous et al, 2007).…”

The Membrane Attack Complex/Perforin Superfamily

“…Using a common MACPF domain for pore formation, proteins associated with the membrane attack complex control microbial invasion of the host through pathogen lysis via formation of a C5b-9 pore complex, a process known as C3-mediated opsonization [Wang et al, 2000]. Other apextrin-like proteins containing the MACPF domain are known to play a role in larval development in eukaryotes such as the sea urchin, Heliocidaris erhthrogramma , and the Mediterranean mussel, Mytilus galloprovincialis [Dheilly et al, 2011; Estevez-Calvar et al, 2011; Haag et al, 1999; Kobayashi et al, 2014]. Furthermore, the MACPF proteins, DBCCR-1 and BRINP-1 (TC 1.C.39.17), are believed to function in both tumor suppression and neural development [Kawano et al, 2004; Kobayashi et al, 2014; Wright et al, 2004].…”