Dyrk1a normalization in Ts65Dn pups did not improve all abnormal phenotypes, perhaps because of developmental dysregulation between Dyrk1a RNA and DYRK1A protein levels, involvement of other trisomic genes, or improvements in only adult mice.
Abstract
Children with Down syndrome (DS) experience delays in cognitive, physical, and motor development. Overexpression of Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), a gene on human chromosome 21 (Hsa21) and triplicated in individuals with Trisomy 21, contributes to neurodevelopmental delays associated with DS, and is a candidate for therapies to improve neurodevelopmental phenotypes. Male and female Ts65Dn DS model pups are trisomic for ∼100 Hsa21 orthologs including Dyrk1a, and both sexes show significant DYRK1A overexpression on postnatal day 6 (P6) in the hippocampus, cerebral cortex, and cerebellum. This study tested the hypothesis that normalization of Dyrk1a copy number in Ts65Dn pups prior to P6 would diminish physical and behavioral developmental outcomes in Ts65Dn mice, thus providing a standard of comparison for success of interventions targeting Dyrk1a. At P3-P21, Ts65Dn compared to euploid pups showed sex-specific deficits in physical, motor, and behavioral development. Male Ts,Dyrk1a+/+/Dox-Cre mice showed improved emergence to running on P19, and both sexes of Ts,Dyrk1a+/+/Dox-Cre mice exhibited reduced isolation-induced ultrasonic vocalizations during the second postnatal week. Dyrk1a normalization in Ts65Dn pups did not improve all abnormal phenotypes, perhaps because of developmental dysregulation between Dyrk1a RNA and DYRK1A protein levels, involvement of other trisomic genes, or improvements in only adult mice.
Trisomy 21 or Down syndrome (DS) affects multi-organ systems across the lifespan. The presence of an extra chromosome, along with genome dosage imbalance due to triplicated genes, contributes to the DS phenotypes. Of the DS mouse models, few are aneuploid with a freely segregating extra chromosome. We previously showed that the aneuploid Ts65Dn mice exhibit metabolic deficits consistent with the metabolic profile of DS. However, the genotype-phenotype relationships in Ts65Dn mice are complicated by the presence of triplicated genes unrelated to human chromosome 21 (Hsa21). To address this issue, we leveraged a refined model, Ts66Yah, where the extra triplicated genes in Ts65Dn have been removed. Deep phenotyping and multi-omics analyses showed that Ts66Yah mice develop pronounced and widespread metabolic disturbances. Despite sexual dimorphism in weight gain, body temperature, lipid and lipoprotein profiles, hepatic injury and adipose fibrosis, both male and female Ts66Yah mice share a common phenotype of pronounced glucose intolerance and insulin resistance, reduced mitochondrial respiratory capacity in visceral fat, altered serum inflammatory cytokine profile, and dysregulated serum and liver metabolomes. Pan-tissue transcriptomes also reveal signatures of immune activation, disrupted metabolic processes and cellular respiration, altered cytokine signaling, enhanced oxidative stress, and extracellular matrix remodeling. These combined changes across tissues disrupt metabolic homeostasis more severely in Ts66Yah than in Ts65Dn mice. Several phenotypes, including glucose intolerance, insulin resistance, tissue fibrosis, and oxidative stress were further exacerbated by an obesogenic diet. This foundational data establishes Ts66Yah as a valuable reference model for the mechanistic and comparative study of metabolic dysfunction in DS.
Muzna Saqib, Fangluo Chen, Diya K. Mistri et al.· bioRxiv· 0 citations
Placental mammal-specific box C/D small nucleolar RNA (SNORD) genes within the imprinted human 15q11q13 domain have garnered increasing attention because their poorly understood roles in the brain and their potential involvement in Prader-Willi syndrome (PWS). Using two novel knockout (KO) mouse models, we demonstrate that combined deletion of Snord116 and Snord115 genes, but not the intervening Ipw ncRNA gene, leads to partially penetrant perinatal lethality (40-50%). Snord116/115-deficient neonates display postnatal growth impairment, hypoglycemia and endocrine dysregulation, including failure of the postnatal leptin surge. Despite showing no overt alterations in feeding behavior, adult Snord116/115-KO mice recapitulate most phenotypes previously reported in Snord116-KO models. RNA-seq analyses of the hypothalamus, prefrontal cortex and cerebellum reveal limited global changes. However, we observed upregulation of two of the most compelling putative RNA targets of Snord116 and Snord115 (Dgkk and Htr2c, respectively) in the postnatal hypothalamus. Nevertheless, no evidence was found to support efficient Snord115-guided ribose methylation of Htr2c mRNA. Finally, comparative analyses across 64 representative placental mammal species reveal that many PWS-associated SNORD genes, including SNORD115, display greater evolutionary changes than previously appreciated, raising questions about the functional relevance and evolutionary selective pressures that have shaped the diversification of certain family members across species. Overall, our study provides an unbiased re-assessment of the evolutionary, molecular and physiological significance of the paternally expressed Snord116-Ipw-Snord115 genomic interval and highlights the early postnatal period as a critical, yet largely underexplored, developmental window during which recently evolved SNORDs likely function as dispensable fine-tuners of gene expression.
V. Marty, Jade Hebras, Raphael Boursereau et al.· bioRxiv· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and restricted, repetitive behaviors, often accompanied by motor, cognitive, and anxiety-related alterations. Although ASD is diagnosed more frequently in males than females, females remain underrepresented in preclinical studies, limiting understanding of sex-dependent phenotypes. The BTBR T+ Itpr3tf/J (BTBR) mouse strain is a widely used animal model of ASD, yet its sex-specific behavioral profiles across functional domains remain incompletely characterized. Here, we conducted a systematic, multi-domain behavioral assessment in male and female BTBR mice and wild-type (WT) controls, examining action control, motor learning, social behavior, and anxiety-related exploration. Despite normal acquisition of instrumental responding, BTBR mice exhibited altered action control characterized by reduced habitual responding and persistent sensitivity to action-outcome contingencies following extended habit training, with effects being more pronounced in females. In the accelerating rotarod task, BTBR mice displayed impaired motor learning that was more prominent in males, whereas performance under constant-speed conditions indicated largely preserved baseline motor coordination. Social impairments were dimension-specific: BTBR males showed delayed initiation of social investigation, whereas BTBR females exhibited reduced social engagement. In the elevated plus maze (EPM), overall genotype effects were modest; However, sex-dependent differences emerged within BTBR strain, suggesting altered exploratory behavior and risk-assessment strategies rather than generalized anxiety-like behavior. Together, these findings identify domain- and sex-specific alterations in action selection, motor learning, social behavior and anxiety-related exploration in BTBR mice. These results highlight the importance of sex-stratified analyses in preclinical ASD research and provide a behavioral framework for investigating the mechanisms underlying ASD-relevant phenotypes.
Unknown authors· Frontiers in Behavioral Neur...· 0 citations
Drosophila models of CSNK2A1 and CSNK2B expression are generated to functionally assess variant impact, and Wnt agonists partially rescue phenotypes associated with adult-specific neuronal reduction of CkII, finding that neuronal and glial CkII is critical for organismal development.
Yina Her, Danielle M Pascual, Ying Lao et al.· bioRxiv· 0 citations
Background Individuals with Down syndrome (DS), caused by triplication of chromosome 21 (Hsa21), face a significantly increased risk of early-onset Alzheimer's disease (AD) and epilepsy. However, the specific impact of Hsa21 genes on these risks is not yet fully understood. Objective To investigate how triplication of mouse chromosome 16 (Mmu16), homologous to Hsa21, affects amyloid-β (Aβ) accumulation in the brain and epileptic seizures in AD-DS model mice. Methods To generate AD-DS model mice, we crossed a mouse model of aspects of AD—an APPswe/PS1dE9 mouse exhibiting brain Aβ accumulation and sudden death associated with epileptic seizures with DS mouse models carrying an extra copy of partial segments of mouse chromosome 16. We used three DS model lines: Ts1Cje, harboring a triplicated region encoding ∼70 Hsa21-homologous genes (Scaf4-Zbtb21); Ts1Rhr with triplication of the Cbr3-Fam3b region; and a newly developed Ts1Kei mouse carrying an extra copy of the Scaf4-Cbr1 region. Aβ accumulation was assessed by immunohistochemistry and enzyme-linked immunosorbent assay. Results Compared with APPswe/PS1dE9 mice, Aβ deposition and insoluble Aβ levels in the brain decreased in APPswe/PS1dE9-Ts1Cje mice but not in APPswe/PS1dE9-Ts1Rhr mice. The high mortality in APPswe/PS1dE9 mice was suppressed by either Ts1Cje- or Ts1Rhr-triplicated region. Despite a tendency for decreased Aβ accumulation in APPswe/PS1dE9-Ts1Kei mice, the study could not be finished due to the extremely high mortality. Conclusions The trisomic region in Ts1Kei mice is suggested to harbor genes associated with decreased Aβ accumulation. Alternatively, the trisomic region in Ts1Rhr mice contains genes suppressing sudden death in APPswe/PS1dE9 mice.
Keiichi Ishihara, Haruka Yasui, Koki Harada et al.· Journal of Alzheimer's Disea...· 0 citations
This work establishes the first domain-resolved in vivo rodent models of NEDBA and provides a validated translational platform for mechanistic investigation and preclinical therapeutic testing.
Camerron M. Crowder, Lyndsay R Watkins, Alexa R. Geltzeiler et al.· bioRxiv· 0 citations
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