Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Roberson, Robin; Toso, Laura; Abebe, Daniel; Spong, Catherine Y.

doi:10.1016/j.ajog.2008.01.033

Cited by 15 publications

(9 citation statements)

References 22 publications

(14 reference statements)

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“…We found no differences between the Hp1bp3 KO and WT mice on these measures, suggesting that the effects of Hp1bp3 KO reported herein are not due to gross behavioral abnormalities. Other positional candidates identified in the CFM QTL, such as Pink1 and Kif17 (Table 1), have been linked to cognitive deficits (Roberson, et al, 2008) and neurodegeneration (Moisoi, et al, 2014) and contain variants that could impact gene function or expression. Here, we focused on genetic correlates of CFM expressed in the hippocampus due to the hippocampal-dependent nature of contextual fear conditioning (Chen, et al, 1996) and the fact that the hippocampus is one of the first structures affected in aging (Burke and Barnes, 2006; Gant, et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Neuner

Garfinkel

Wilmott

et al. 2016

Neurobiology of Aging

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An individual’s genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice, and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.

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Section: Discussionmentioning

confidence: 99%

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Neuner

Garfinkel

Wilmott

et al. 2016

Neurobiology of Aging

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“…Therefore, it will be important to investigate the time frame of NMDAR phosphorylation changes after MK‐801 treatment, as well as phosphorylation of other sites within NR1 and other NMDAR subunits. Alternatively, Roberson et al (2008) recently postulated a role for impaired trafficking of the NR2B subunit in Ts65Dn based on their observation of a significant decrease compared with controls in the levels of the kinesin motor protein, KIF17. While levels of both NR2B and NR2A were normal in Ts65Dn mice, as measured in whole brain lysates, this does not rule out possible abnormalities in distribution or dynamics of trafficking.…”

Section: Discussionmentioning

confidence: 99%

Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK‐801

Siddiqui

Lacroix

Stasko³

et al. 2008

Genes Brain and Behavior

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Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21-encoded, confirmed protein-coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the highaffinity N-methyl-D-aspartate (NMDA) receptor (NMDAR) channel blocker, MK-801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR-mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 proteincoding genes, is also hypersensitive to MK-801. To investigate the molecular basis for the responses to MK-801, we have measured levels of a subset of chr21 and phosphorylated non-chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK-801. We show that in euploid mice, the chr21-encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK-801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naïve, unstimulated mice, and the MK-801-induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain-region-specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.

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“…In a Ts65Dn mouse model of Down syndrome that bears a triplicated segment of chromosome 16, which shares >50% homology with human chromosome 21, a significant decline in the level of KIF17 is found in the brain [129]. These animals exhibit a number of developmental, learning, and behavioral deficits found in Down syndrome [130, 131].…”

Section: Diseases and Pathologies Related To Kif17mentioning

confidence: 99%

“…These animals exhibit a number of developmental, learning, and behavioral deficits found in Down syndrome [130, 131]. However, the true cause of learning deficits in these animals is not clear, as the levels of both NR2B and NR2A are reportedly unchanged [129]. Long-term potentiation, as induced by in vitro high-frequency stimulation of hippocampal neurons in adult Ts65Dn mice, is either reduced [132] or unchanged [133].…”

Section: Diseases and Pathologies Related To Kif17mentioning

confidence: 99%

The kinesin superfamily protein KIF17: one protein with many functions

Wong‐Riley

Besharse²

2012

BioMolecular Concepts

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Kinesins are ATP-dependent molecular motors that carry cargos along microtubules, generally in an anterograde direction. They are classified into 14 distinct families with varying structural and functional characteristics. KIF17 is a member of the kinesin-2 family that is plus end-directed. It is a homodimer with a pair of head motor domains that bind microtubules, a coiled-coil stalk, and a tail domain that binds cargos. In neurons, KIF17 transports N-methyl-D-aspartate receptor NR2B subunit, kainate receptor GluR5, and potassium Kv4.2 channels from cell bodies exclusively to dendrites. These cargos are necessary for synaptic transmission, learning, memory, and other functions. KIF17’s interaction with NXF2 enables the transport of mRNA bidirectionally in dendrites. KIF17 or its homolog OSM-3 also mediates intraflagellar transport of cargos to the distal tips of flagella or cilia, thereby aiding in ciliogenesis. In many invertebrate and vertebrate sensory cells, KIF17 delivers cargos that contribute to chemosensory perception and signal transduction. In vertebrate photoreceptors, KIF17 is necessary for outer segment development and disc morphogenesis. In the testis, KIF17 (KIF17b) mediates microtubule-independent delivery of ACT from the nucleus to the cytoplasm and microtubule-dependent transport of Spatial-ε, both are presumably involved in spermatogenesis. KIF17 is also implicated in epithelial polarity and morphogenesis, placental transport and development, and the development of specific brain regions. The transcriptional regulation of KIF17 has recently been found to be mediated by nuclear respiratory factor 1 (NRF-1), which also regulates NR2B as well as energy metabolism in neurons. Dysfunctions of KIF17 are linked to a number of pathologies.

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Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Cited by 15 publications

References 22 publications

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK‐801

The kinesin superfamily protein KIF17: one protein with many functions

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