MeCP2 is required for activity-dependent refinement of olfactory circuits

Degano, Alicia L.; Park, Min J.; Judith, Penati; Qun, LI; Ronnett, Gabriele V.

doi:10.1016/j.mcn.2014.01.005

Cited by 31 publications

(30 citation statements)

References 100 publications

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“…Patients with Rett Syndrome are typically characterized by a normal development at birth and subsequent failure to thrive leading to microcephaly and intellectual disability that develops with age. As a result, Rett Syndrome is thought to be caused by experience-dependent loss of neuronal function, which would correlate with data suggesting that MECP2 regulates activity dependent gene expression 10,13,37 . The microcephaly has been proposed to be a function of decreased nuclear size and dendritic arborization of affected neurons 13,22 .…”

Section: Discussionsupporting

confidence: 53%

Loss of MECP2 leads to activation of p53 and neuronal senescence

Ohashi¹,

Allen²,

Lee³

et al. 2017

Preprint

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27To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic 28 lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient 29 fibroblasts with and without MECP2 expression in an attempt to recapitulate disease 30 phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression 31 changes including induction of a Senescence Associated Secretory Phenotype (SASP) 32 program. Patient derived Neurons made without MECP2 show signs of stress, including 33 induction of p53, and senescence. The induction of p53 appeared to affect dendritic 34 branching in Rett neurons, as p53 inhibition restored dendritic complexity. These 35 disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to 36 an increase in aspects of neuronal aging. 37 38 39 40 41 42 43 44 45 46Rett Syndrome is a disease associated with loss of function mutations in the gene 48 MECP2, which was originally identified as encoding a methylated DNA binding protein 1-49 3 . Patient symptoms include microcephaly, intellectual disability, facial dysmorphia, and 50 seizure activity 4,5 . Studies in murine models recapitulate many of the patient phenotypes 51 and have recently identified a role for MECP2 particularly in inhibitory neurons [6][7][8][9] . These 52 studies demonstrated that loss of MECP2 can lead to defects in transcription 10-12 , 53 dendritic branching 13 , nuclear size 3 , and AKT signaling 14 .54 55 MECP2 has also been described as a transcription factor with specific targets 10,11,13 , and 56 more broadly as either a transcriptional activator 14 or repressor [15][16][17][18] . However, despite 57 decades of research on MECP2, it is still unclear how mutations in this protein lead to 58 patient symptoms 3,14,[19][20][21] . To confirm findings made in other models and further study 59 these in a human system, some have turned to modeling Rett Syndrome in vitro by taking 60 advantage of Disease in a dish approaches. This involves making hiPSCs from patient 61 somatic cells, or using genome engineering to introduce mutations into WT human 62 pluripotent stem cells. In either case, the pluripotent stem cells created are then 63 differentiated toward the neural lineage, and then comparisons can be made between 64 cells that express MECP2 or lack it. 65 66 Some of these studies have even taken advantage of isogenic or congenic cells lines to 67 identify both transcriptional and electrophysiological effects of loss of MECP2 in human 68 4 in vitro models 14,22 . In the current study, we also sought to mitigate the effect of genetic 69 background and variability of differentiation by taking advantage of several congenic lines 70 of hiPSCs that either express the WT allele or the mutant allele leading to cells that 71 express or lack MECP2 23 . This allowed for detailed molecular analyses of hiPSCs, NPCs 72 and neurons with and without MECP2 under the same genetic background. In addition, 73 several lines were made and analyzed in each category to avoid vari...

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Section: Discussionsupporting

confidence: 53%

Loss of MECP2 leads to activation of p53 and neuronal senescence

Ohashi¹,

Allen²,

Lee³

et al. 2017

Preprint

View full text Add to dashboard Cite

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“…It is also worth noting that MECP2 mutations cause structural changes of brain neurons, often described as more dense and packed (Jentarra et al, 2010). Recent findings have also documented pronounced changes in sensory olfactory and trigeminal neurons (Degano, Park, Penati, Li, & Ronnett, 2014) providing further evidence of the importance of MeCP2's role in activity-dependent maturation of sensory circuitry. Although speculative, it may be that the complex morphological ENF observations reflect dorsal root ganglion (DRG) neuron abnormalities, as suggested also by Bhattacherjee et al (2017) in their documented pattern of somatosensory deficits associated with MECP2 mutation, that appear to be cell-autonomous to primary sensory neurons of the DRG.…”

Section: Discussionmentioning

confidence: 89%

A clinical case–control comparison of epidermal innervation density in Rett syndrome

et al. 2019

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Introduction Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10–15,000 female live births), is most often caused by loss‐of‐function mutations in the X‐linked methyl‐CpG‐binding protein 2 gene ( MECP2 ). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. Methods We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients ( N = 4, aged 12–19 years) against an archived approximate age‐, sex‐, body‐site matched comparison sample of healthy adolescent females ( N = 8, ages 11–17). Results Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co‐stained calcitonin gene‐related protein [CGRP]) innervation density compared with healthy female control individuals. Conclusions Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.

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“…Their families report often that they are using eye contact as communication method and therefore eye tracking systems are a promising method to improve communication.Molecular/histological data: MECP2 deficiency induces also an imbalance in glutamatergic/GABAergic innervation in the olfactory bulb. The excitation in MECP2 KO mice is reduced and there is generally an imbalance between excitatory and inhibitory pathways observed leading to premature death of olfactory neurons in RTT mice models [121]. MECP2 seems to regulate the activity dependent transcriptional responses in olfactory sensory neurons the same way as in central nervous system and model systems [123].…”

Section: Current Gaps In Understanding Rtt Pathwaysmentioning

confidence: 99%

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6–18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

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MeCP2 is required for activity-dependent refinement of olfactory circuits

Cited by 31 publications

References 100 publications

Loss of MECP2 leads to activation of p53 and neuronal senescence

Loss of MECP2 leads to activation of p53 and neuronal senescence

A clinical case–control comparison of epidermal innervation density in Rett syndrome

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

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