Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

Abstract

BackgroundThe mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour.MethodsWe performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homo- and heteroscedatic T-tests.ResultsFemale transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates.ConclusionOur results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates.

The Extracellular Signal-Regulated Kinase 3 (Mitogen-Activated Protein Kinase 6 [MAPK6])–MAPK-Activated Protein Kinase 5 Signaling Complex Regulates Septin Function and Dendrite Morphology

“…Erk3 Ϫ/Ϫ newborn mice that survive neonatal lethality display uncoordinated movements, lack of reflex, diminished ability to suckle, and other phenotypes often correlated with neuronal dysfunction (25,52). In addition, transgenic mice expressing a constitutively active mutant of MK5 develop behavioral abnormalities (13). These observations suggested a neuronal function for the ERK3/MK5 signaling module.…”

“…The transgenic overexpression of constitutively active MK5 (caMK5) in mice led to anxiety-related traits and locomotor differences (13).…”

Septin 8 is an interaction partner and in vitro substrate of MK5

“…MAPK p38, which can act as an upstream activator of MK5 [53] , has been shown to be involved in SNARE-dependent exocytotic release of brain-derived neurotrophic factor from microglia [54] . Finally, transgenic mice overexpressing an active variant of MK5 display different anxiety-related traits as compared to wild-type littermates [5] . All these observations point to a possible role of MK5 in exocytosis that may comprise SEPT8.…”

“…Biological functions of MK5 are poorly understood despite the high similarity in structure with other widely studied members of the subgroup [3] . Recent studies have highlighted the importance of MK5 in ras-induced senescence, antiproliferation, tumor suppression, anxiety-related behavior, energy-depletioninduced suppression of mammalian target of rapamycin C1, rearrangements of the cytoskeleton, endothelial cell migration, and tumor angiogenesis [4][5][6][7][8][9] . Several bona fide substrates have been identified, including extracellular signal-regulated kinase (ERK)3, ERK4, 14-3-3ε, p53, Ras homolog enriched in brain (Rheb) and heat shock protein (Hsp)27 [6,8,[10][11][12][13][14][15] .…”

“…These GTP-binding proteins are involved in diverse processes such as cytokinesis, membrane remodeling and compartmentalization, cytoskeleton rearrangement, vesicle trafficking, and apoptosis [18,20,21] . Knockout mice have been generated for SEPT3, 4,5,6, 7 and 9 genes [22] .…”