Trim9Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

Abstract

During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9 Ϫ/Ϫ adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9 Ϫ/Ϫ mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors.

Frazzled promotes growth cone attachment at the source of a Netrin gradient in the Drosophila visual system

“…To do this, we assessed the function of another gene in the Net-DCC pathway that has cell-autonomous function. Trim9 has been identified as a component of Net-DCC signaling in neural development in both vertebrates and invertebrates (Alexander et al, 2010; Hao et al, 2010; Morikawa et al, 2011; Song et al, 2011; Winkle et al, 2016, 2014). Trim9 interacts through its SPRY domain with the Fra C-terminal cytoplasmic tail (Morikawa et al, 2011).…”

“…In addition, we present evidence suggesting that R8 growth cones can recognize the target layer without Net-Fra . Instead, Netrin, DCC, and TRIM9, a signaling component directly downstream from DCC (Alexander et al, 2010; Hao et al, 2010; Morikawa et al, 2011; Song et al, 2011; Winkle et al, 2016, 2014), are essential for attachment of a single leading process extended from R8 growth cones to the target layer. We propose that R8 growth cones reach and recognize the target layer independent of Fra, adhere to the target layer in a Fra-dependent step, and this adhesion is consolidated by a TRIM9-dependent step.…”

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

“…In patients with dementia and Lewy bodies, TRIM9 expression in the brain is reduced [9]. Furthermore, in animal models, absence of TRIM9 causes excessive dendrite arborization, mislocalization and decreased dendritic density in adult born neurons of the dentate gyrus, leading to impairment of learning and memory [18]. TRIM67 interacts with TRIM9 and DCC and plays important role in brain development and behavior, including learning and memory and cognitive flexibility [6].…”

Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis

“…The data were represented in voxel volume for all the 3D–pipes measured in the ROIs, and were normalized with the DG volume (calculated in ImageJ). For retrovirus analysis, dendrites were analyzed using the plugin “Simple Neurite Tracer” in ImageJ (Schindelin et al, 2012; Winkle et al, 2016). Sholl analysis was performed by counting the number of crossings by dendrites of concentric circles originating at the soma with increasing radii of 10 µm in ImageJ (Winkle et al, 2016).…”