Ube3a mRNA and protein expression are not decreased in Mecp2 mutant mice

Lawson-Yuen, Amy; Liu, Daniel; Han, Liqun; Jiang, Zhong‐Xing; Tsai, Guochuan E.; Basu, Alo C.; Picker, Jonathan; Feng, Jiamin; Coyle, Joseph T.

doi:10.1016/j.brainres.2007.08.039

Cited by 68 publications

(52 citation statements)

References 30 publications

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“…These mice were on a C57Bl/6 background. Mecp2 R168X/+ and Mecp2 +/+ mice (Lawson-Yuen et al, 2007) were a kind gift from Joanne E Berger-Sweeney at Tufts University. These mice were on a mixed C57Bl/6 × 129S6/SvEv Tac background.…”

Section: Methodsmentioning

confidence: 99%

“…In the first mouse model, conversion of threonine 158 to methionine or alanine (T158M or T158A) results in a mutated protein with decreased binding to methylated DNA and that is degraded more rapidly than normal MeCP2 (Goffin et al, 2011). In the second model, a knockin of a stop codon at arginine 168, mimicking a nonsense R168X mutation, yields an early truncated MeCP2 protein that retains the MBD domain, but the TRD domain is lost (Brendel et al, 2007) (Lawson-Yuen et al, 2007). We characterized the respiratory patterns in female heterozygotes with either the MeCP2 T158A ( Mecp2 T158A/+ ) or MeCP2 R168X ( Mecp2 R168X/+ ) mutation.…”

Section: Introductionmentioning

confidence: 99%

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Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

et al. 2014

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Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only ~10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2T158A/+) or a nonsense mutation R168X (Mecp2R168X/+). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2T158A/+ and Mecp2R168X/+ heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild type controls. Interestingly, the incidence of apnea was much greater in Mecp2R168X/+ heterozygotes, 189 per hour, than Mecp2T158A/+ heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

et al. 2014

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“…Similarly, the mouse models harboring known RTT-causing MECP2 mutations have been helpful in determining the role of these mutations in RTT pathology. The examples include, the mutations which result in truncated MeCP2 protein (MeCP2 308 and R168X) (Shahbazian et al 2002a;Schaevitz et al 2013;Lawson-Yuen et al 2007) as well as mutations which cause loss of function or loss of protein/DNA interactions (MECP2 T308A, MECP2 R306C and MECP2 T158A) (Lyst et al 2013;Goffin et al 2011;Ebert et al 2013). …”

Section: Mouse Models To Study Rett Syndromementioning

confidence: 99%

Rett Syndrome and MeCP2

2014

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Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

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“…There is a controversial correlation of MeCP2 expression with GABRB3 expression, which is evident in the three neuropathies (Angelman syndrome, ASD and Rett's syndrome); MeCP2 deficiency in these disorders causes a decreased expression of GABRB3 [109,112,113]. However, other studies challenge this finding by showing no significant reduction in GABRB3 mRNA and protein levels in brain tissues of MeCP2-deficient mice [114,115]. LaSalle reasons the time point of MeCP2-deficient mice used or RT-PCR issues to explain the discrepancies observed in these later studies [105,106,116].…”

Section: Mecp2 - Additional Regulations In Gabaergic Neurotransmissionmentioning

confidence: 99%

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Shrestha

Offer²

2016

Med Epigenet

6,446

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The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotransmission, both excitatory and inhibitory, in neurogenesis and central nervous system development including its control of neuronal cell proliferation and migration, synaptogenesis, dendrite formation and branching, and new neuronal cell integration in the adult brain. There has been remarkable progress in understanding the epigenetic regulations of GABAergic genes and their aberrant expressions in various neurological disorders such as autism spectrum disorder, Rett's syndrome, schizophrenia and PWS. The roles of histone modifications, chromatin looping and gene methylation have been implicated in altered regulations of key genes in the GABAergic pathway. Taken together, they affect the functioning of GABAergic neurotransmission and disrupt various events in brain development. Here, we focus on the role of GABAergic neurotransmission in brain development and on how various genetic and epigenetic events regulate the GABAergic genes in pre- and postnatal brain. We also discuss how these regulatory mechanisms contribute to the pathogenesis of neurological disorders and, therefore, can be used in the development of potential epigenetic therapy for these diseases.

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Ube3a mRNA and protein expression are not decreased in Mecp2 mutant mice

Cited by 68 publications

References 30 publications

Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

Rett Syndrome and MeCP2

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

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