Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

Wang, Jieqi; Wegener, Eike; Huang, Teng-Wei; Sripathy, Smitha; Jesús-Cortés, Héctor De; Xu, Pin; Tran, Stephanie; Knobbe, Whitney; Leko, Vid; Britt, Jeremiah K.; Starwalt, Ruth; McDaniel, Lisa D.; Ward, Chris S.; Parra, Diana; Newcomb, Benjamin; Lao, Uyen; Nourigat, Cynthia; Flowers, David; Cullen, Shay; Jorstad, Nikolas L.; Yang, Yue; Glaskova, Lena; Vigneau, Sébastien; Kozlitina, Julia; Yetman, Michael J.; Jankowsky, Joanna L.; Reichardt, Sybille D.; Reichardt, Holger M.; Gärtner, Jutta; Bartolomei, Marisa S.; Fang, Min; Loeb, Keith R.; Keene, C. Dirk; Bernstein, Irwin D.; Goodell, Margaret A.; Brat, Daniel J.; Huppke, Peter; Neul, Jeffrey L.; Bedalov, Antonio; Pieper, Andrew A.

doi:10.1038/nature14444

Cited by 167 publications

(99 citation statements)

References 12 publications

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“…Interestingly, it has been shown that phagocytic activity of the WT bone marrow-derived cells is necessary to rescue the Rett syndrome phenotype. In contrast, other studies investigating the function of microglia in the development of Mecp2 deficiency-induced Rett syndrome revealed enhanced phagocytosis of dendritic spines during synaptic pruning that is not rescued by reintroduction of Mecp2 into microglia (77,78). These studies suggest a contribution of microglia in disease pathology, but other mechanisms of disease could also be involved.…”

Section: Physiological Function Of Microglia In the Adult Braincontrasting

confidence: 44%

Microglia in steady state

Kierdorf¹,

Prinz²

2017

Journal of Clinical Investigation

227

179

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Section: Physiological Function Of Microglia In the Adult Braincontrasting

confidence: 44%

Microglia in steady state

Kierdorf¹,

Prinz²

2017

Journal of Clinical Investigation

227

179

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“…We previously described a transgenic mouse model for monitoring MeCP2 expression with a fusion of the MeCP2 gene with firefly luciferase and hygromycin resistance genes (MeCP2-FL-HR) (12). Whereas the fusion protein proved unstable, resulting in a MeCP2 loss-of-function phenotype in mice, the reporter expression pattern paralleled the expression of the native MeCP2 gene (12).…”

Section: Resultsmentioning

confidence: 99%

“…Whereas the fusion protein proved unstable, resulting in a MeCP2 loss-of-function phenotype in mice, the reporter expression pattern paralleled the expression of the native MeCP2 gene (12). To develop clonal cell lines that have the transgene on either the active (Xa) or inactive X chromosome, we immortalized tail tendon fibroblasts from heterozygous MeCP2-FL-HR/MeCP2 female mice.…”

Section: Resultsmentioning

confidence: 99%

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Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

Sripathy

Leko

Adrianse

et al. 2017

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

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Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-β pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-β signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.XIST | X inactivation | MeCP2 | Rett syndrome | BMP/TGF-β

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“…Some studies have suggested that non-neuronal CNS cells such as astrocytes and microglia play a crucial role in the RTT phenotype and that repair of these cells alone provides robust phenotype amelioration [111,139,140]. While HR levels in these dividing cells will be higher than in neurons it will not be enough to compensate for the vastly greater number of cells that will be repaired imprecisely by NHEJ.…”

Section: Other Gene-targeted Strategies In Rttmentioning

confidence: 99%

Gene Therapy for Rett Syndrome: Prospects and Challenges

et al. 2015

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Rett syndrome (RTT) is a neurological disorder that affects females and is caused by lossof-function mutations in the X-linked gene MECP2. Deletion of Mecp2 in mice results in a constellation of neurological features that resemble those seen in RTT patients. Experiments in mice have demonstrated that restoration of MeCP2, even at adult stages, reverses several aspects of the RTT-like pathology suggesting that the disorder may be inherently treatable. This has provided an impetus to explore several therapeutic approaches targeting RTT at the level of the gene, including gene therapy, activation of MECP2 on the inactive X chromosome and read-through and repair of RTT-causing mutations. Here, we review these different strategies and the challenges of gene-based approaches in RTT.

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Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

Cited by 167 publications

References 12 publications

Microglia in steady state

Microglia in steady state

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

Gene Therapy for Rett Syndrome: Prospects and Challenges

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