Treating Rett syndrome: from mouse models to human therapies

Vashi, Nisha; Justice, Monica J.

doi:10.1007/s00335-019-09793-5

Cited by 76 publications

(99 citation statements)

References 209 publications

(192 reference statements)

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“…The major reason for this shortcoming is the time-taking and costly procedures involved in developing transgenic mice with the desired mutations. Nevertheless, transgenic mouse models for some of the disease-associated mutations have been developed, characterized and used for testing drugs / small molecules for improving the phenotypes [3] , [4] , [5] Despite these efforts, many mutations still need to be investigated. Additional challenges include the inability to determine defects in neurodevelopmental stages for mutations that cause embryonic lethality.…”

Section: Methods Detailsmentioning

confidence: 99%

Reproducible differentiation and characterization of neurons from mouse embryonic stem cells

2020

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Investigation on the effects of disease-associated mutations on neurodevelopment is an essential approach to understand the molecular basis of neurological disorders and can be achieved by generating suitable animal models. However, some of the mutations preclude development of animal models, leaving cell-based models as the only options. Mouse embryonic stem cells (mESCs) are attractive because of the well-established technologies for introducing disease-associated mutations and the feasibility of investigating the abnormalities during different stages of neurogenesis. Importantly, such transgenic mESCs enable large-scale screening and identification of the most promising small molecules and/or drug candidates before undertaking expensive animal studies. Although neuronal differentiation from mESCs is one of the earliest methods to be developed, we observed that the published as well as publicly available methods did not yield neurons consistently. Here, we describe a 16-day differentiation protocol that consistently induced differentiation of mESCs into neurons. This step-wise protocol enables monitoring of the neuronal differentiation process at different stages as well as characterization using the markers for immature and mature neurons by using immunocytochemistry and quantitative real-time PCRs. Development of a method for differentiating mouse ES cells into neurons. Differentiating the mouse ES cells into embryoid bodies prior to induction of neuronal differentiation results in better neuron formation.

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Section: Methods Detailsmentioning

confidence: 99%

Reproducible differentiation and characterization of neurons from mouse embryonic stem cells

2020

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“…The transcription factor MECP2 regulates expression of a wide range of genes and is emerging as an important regulator of metabolic homeostasis [9,12,13]. Prior to symptom onset, brain cholesterol is increased, and statins were found to ameliorate motor symptoms and to extend lifespan in Mecp2 -mutant mice [9].…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid Metabolism Perturbations in Rett Syndrome

et al. 2019

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Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.

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“…Murine cellular model systems include differentiated cells from embryonic stem cells or primary neural stem cells [ 67 ]. For detailed information on different RTT model systems, we refer the readers to excellent recent reviews [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ].…”

Section: Biological Systems To Study Rett Syndromementioning

confidence: 99%

Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

Pejhan

Rastegar

2021

Biomolecules

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Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

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Treating Rett syndrome: from mouse models to human therapies

Cited by 76 publications

References 209 publications

Reproducible differentiation and characterization of neurons from mouse embryonic stem cells

Reproducible differentiation and characterization of neurons from mouse embryonic stem cells

Sphingolipid Metabolism Perturbations in Rett Syndrome

Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

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