DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects

Ahn, Kyoung-Jin; Jeong, Hey Kyeong; Choi, Hansaem; Ryoo, Soo‐Ryoon; Kim, Yeon Ju; Goo, Jun-Seo; Choi, Se‐Young; Han, Jung‐Soo; Ha, Ilho; Song, Woo-Joo

doi:10.1016/j.nbd.2005.12.006

Cited by 205 publications

(208 citation statements)

References 49 publications

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“…DYRK1A transgenic (Tg) mouse models were also made in an effort to reveal its role in DS. Cognitive deficits were noted in two models overexpressing DYRK1A, one under the sheep metallothionein 1a (sMT-1a) promoter (24) and the other in a BAC under the human DYRK1A promoter (23). Although original reports of these two models did not mention changes in body weight, a recent study showed that DYRK1A BAC Tg mice are lean and resistant to diet-induced obesity (62).…”

Section: Discussionmentioning

confidence: 99%

“…It binds DYRK1A, a dual-specificity tyrosine phosphorylationregulated kinase that is encoded by a gene located on chromosome 21 and is overexpressed in Down syndrome (DS) (22). DYRK1A is a major candidate gene in producing features of DS, and transgenic mice overexpressing DYRK1A show cognitive and behavioral alterations similar to those in persons with DS (23,24). Also, recent studies show that administration of epigallocatechin-3-gallate (EGCG), which antagonizes DYRK1A, can improve the cognitive function of individuals with DS (25,26).…”

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confidence: 99%

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DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.H untingtin-associated protein 1 (Hap1) is a cytoplasmic protein highly expressed in neurons of the CNS (1, 2). Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11). The function of Hap1 is also age dependent and appears to be important for postnatal neurogenesis in the paraventricular nuclei, the lateral hypothalamus (5, 11), and the dentate gyrus of the hippocampus (7).The specific function of Hap1 in the hypothalamus may be associated with unique cytoplasmic structures called "stigmoid bodies" (SBs), which are formed by Hap1 in the hypothalamus (12, 13) and appear to be non-membrane-bound, ovoid to circular in shape, and 0.5-3 μm in diameter (14,15). Widely regarded as a determinant marker for SBs, Hap1 is capable of sequestering several important disease-related proteins into SB-like inclusions in cell cultures, including Abelson helper integration site 1 (Ahi1), androgen receptor, TBP, and ataxin-3 (6, 16-18). However, in vivo evidence for such sequestration exists only for Ahi1, which is responsible for specific forms of Joubert syndrome. Other proteins, such as SorLA/LR11, sortilin, 5-HT 7 receptor, and 14-3-3, are also reported to be associated with . Although SBs are abundant in the hypothalamus, their functions remain elusive, despite speculation that they might be involved in sex-steroid maturation (15). We bel...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Stereological studies on heterozygous mice with one copy of DYRK1A have shown that changes in the dosage of this gene induce an increase in pyramidal cell density, together with lower levels of dendritic arborization (Benavides-Piccione et al, 2005). A recent study (Ahn et al, 2006) with BAC transgenic mice carrying one extra copy of the human DYRK1A gene also reported phenotypic alterations, including an increase in brain weight and cognitive impairment: these results confirm that the modifications seen in YAC152F7 transgenic mice are due to DYRK1A overexpression and that a change in DYRK1A gene dosage may have both morphological and behavioral consequences.…”

Section: Discussionmentioning

confidence: 99%

Increased Dosage of DYRK1A and Brain Volumetric Alterations in a YAC Model of Partial Trisomy 21

Sebrié

Chabert

Ledru

et al. 2008

The Anatomical Record

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A yeast artificial chromosome (YAC) transgenic murine model of partial trisomy 21 overexpressing five human genes-including DYRK1A, which encodes a serine threonine kinase involved in cell cycle controlhas been shown to present an increase in brain weight. We analyzed this new phenotype by measuring total and regional brain volumes at different ages, using a 7 Tesla magnetic resonance imaging volumetric approach. Volumetric measurements showed a total volume increase of 13.6% in adult mice. Changes in brain morphogenesis were already visible at a very early postnatal stage (postnatal days 2-7). Region-specific changes were characterized from postnatal day 15 to 5 months. These results, made it possible to define region-specific effects of DYRK1A overexpression, with the strongest increase seen in the thalamus-hypothalamus area (24%).

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“…For Down syndromerelated studies, it has the added attraction of being the most commonly used test, providing a robust phenotype in many mouse models (Escorihuela et al 1998;Sago et al 1998;Chabert et al 2004;Martinez-Cue et al 2005;Ahn et al 2006). There are, however, significant drawbacks to using the MWM when assaying a molecular phenotype.…”

Section: Discussionmentioning

confidence: 99%

Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze

Stasko

Costa

et al. 2007

Gene

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The pre-mRNA encoding the serotonin 2C receptor, HTR2C (official mouse gene symbol, Htr2c), is subject to adenosine deamination that produces inosine at five sites within the coding region. Combinations of this site-specific A-to-I editing can produce 32 different mRNA sequences encoding 24 different protein isoforms with differing biochemical and pharmacological properties. Studies in humans have reported abnormalities in patterns of HTR2C editing in psychiatric disorders, and studies in rodents show altered patterns of editing in response to drug treatments and stressful situations. To further explore the biological significance of editing of the Htr2c mRNA and its regulation, we have examined patterns of Htr2c editing in C57BL/6J mice after exposure to the hidden platform version of the Morris Water Maze, a test of spatial learning that, in mice, is also associated with stress. In brains of both swimming controls and mice trained to find the platform, subtle time dependent changes in editing patterns are seen as soon as one hour after a probe trial and typically last less than 24 hours. Changes in whole brain with cerebellum removed differ from those seen in isolated hippocampus and cortex. Unexpectedly, in hippocampi from subsets of mice, abnormally low levels of editing were seen that were not correlated with behavior or with editing levels in cortex. These data implicate responses to spatial learning and stress, in addition to stochastic processes, in the generation of subtle changes in editing patterns of Htr2c.

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DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects

Cited by 205 publications

References 49 publications

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Increased Dosage of DYRK1A and Brain Volumetric Alterations in a YAC Model of Partial Trisomy 21

Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze

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