scholarly journals Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

2021 ◽  
Author(s):  
Andrea Boitnott ◽  
Dévina C Ung ◽  
Marta Garcia-Forn ◽  
Kristi Niblo ◽  
Danielle Mendonca ◽  
...  
Keyword(s):  
Mouse Model ◽  
Behavioral Problems ◽  
Behavioral Changes ◽  
Face Validity ◽  
Motor Deficits ◽  
Projection Neurons ◽  
Loss Of Function ◽  
Cortical Projection ◽  
Glutamatergic Neurons ◽  
Brain Malformations

ABSTRACTBackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis.MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/−) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development.ResultsDdx3x+/− mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex.ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

scholarly journals Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Georgia Panagiotakos ◽  
Christos Haveles ◽  
Arpana Arjun ◽  
Ralitsa Petrova ◽  
Anshul Rana ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Autism Spectrum ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Timothy Syndrome ◽  
Cortical Projection ◽  
Embryonic Mouse ◽  
Syndromic Asd

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

scholarly journals Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta

2021 ◽  
Vol 118 (25) ◽  
pp. e2100690118
Author(s):  
Joohyun Lim ◽  
Caressa Lietman ◽  
Matthew W. Grol ◽  
Alexis Castellon ◽  
Brian Dawson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Osteogenesis Imperfecta ◽  
Genetic Disorder ◽  
Motor Deficits ◽  
Type I ◽  
Loss Of Function ◽  
Pathogenic Mechanisms ◽  
Biochemical Alterations ◽  
Fk506 Binding Protein ◽  
Type I Procollagen

Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 (FKBP10) lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. In this study, we have generated a mouse model in which Fkbp10 is conditionally deleted in tendons and ligaments. Fkbp10 removal substantially reduced telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons. These biochemical alterations resulting from Fkbp10 ablation were associated with a site-specific induction of fibrosis, inflammation, and ectopic chondrogenesis followed by joint deformities in postnatal mice. We found that the ectopic chondrogenesis coincided with enhanced Gli1 expression, indicating dysregulated Hedgehog (Hh) signaling. Importantly, genetic inhibition of the Hh pathway attenuated ectopic chondrogenesis and joint deformities in Fkbp10 mutants. Furthermore, Hh inhibition restored alterations in gait parameters caused by Fkbp10 loss. Taken together, we identified a previously unappreciated role of Fkbp10 in tendons and ligaments and pathogenic mechanisms driving OI joint dysfunction.

scholarly journals Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

2019 ◽  
Vol 20 (24) ◽  
pp. 6251 ◽  
Author(s):  
Yuan-Hao Chen ◽  
Vicki Wang ◽  
Eagle Yi-Kung Huang ◽  
Yu-Ching Chou ◽  
Tung-Tai Kuo ◽  
...  
Keyword(s):  
Gender Differences ◽  
Mouse Model ◽  
Motor Behavior ◽  
Epidemiological Data ◽  
Behavioral Changes ◽  
Motor Deficits ◽  
Female Mice ◽  
Progressive Loss ◽  
Symptom Progression ◽  
Da Release

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson’s disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.

scholarly journals Sex-Related Motor Deficits in the Tau-P301L Mouse Model

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1160
Author(s):  
Luana Cristina Camargo ◽  
Dominik Honold ◽  
Robert Bauer ◽  
N. Jon Shah ◽  
Karl-Josef Langen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Behavioral Changes ◽  
Motor Deficits ◽  
The Novel ◽  
Behavioral Alterations ◽  
Object Recognition Test ◽  
Histological Changes ◽  
Female Mice

The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.

Author response for "Laminar distribution of cortical projection neurons to the pulvinar: A comparative study in cats and mice"

2020 ◽  
Author(s):  
Bruno Oliveira Ferreira de Souza ◽  
Éve‐Marie Frigon ◽  
Robert Tremblay‐Laliberté ◽  
Christian Casanova ◽  
Denis Boire
Keyword(s):  
Comparative Study ◽  
Author Response ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Laminar Distribution

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

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