Normal mitral cell dendritic development in the setting of Mecp2 mutation

Palmer, Amy M.; Degano, Alicia L.; Park, Min J.; Ramamurthy, Santosh; Ronnett, Gabriele V.

doi:10.1016/j.neuroscience.2011.11.044

Cited by 7 publications

(6 citation statements)

References 61 publications

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“…MeCP2 was previously shown to regulate neurite growth and axon targeting in the hippocampus, motor cortex and olfactory system of the mouse ( Matarazzo et al, 2004 ; Belichenko et al, 2009 ; Degano et al, 2009 ; Palmer et al, 2012 ). Thus, we first examined gross axonal projections using an axon marker, acetylated tubulin (AcTub) at 24 h post fertilization (hpf).…”

Section: Resultsmentioning

confidence: 99%

Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2

Leong

Lim

Korzh

et al. 2015

Front. Cell. Neurosci.

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Mutations in the gene encoding the MECP2 underlies Rett syndrome, a neurodevelopmental disorder in young females. Although reduced pain sensitivity in Rett syndrome patients and in partial MeCP2 deficient mice had been reported, these previous studies focused predominantly on motor impairments. Therefore, it is still unknown how MeCP2 is involved in these sensory defects. In addition, the human disease manifestations where males with mutations in MECP2 gene normally do not survive and females show typical neurological symptoms only after 18 months of age, is profoundly different in MeCP2-deficient mouse where all animals survived, and males but not females displayed Rett syndrome phenotypes at an early age. Thus, the mecp2-deficient zebrafish serves as an additional animal model to aid in deciphering the role and mechanisms of Mecp2 in neurodevelopment. Here, we used two independent methods of silencing expression of Mecp2 in zebrafish to uncover a novel role of Mecp2 in trigeminal ganglion sensory neurons during the embryonic development. mecp2-null mutation and morpholino-mediated silencing of Mecp2 in the zebrafish embryos resulted in defects in peripheral innervation of trigeminal sensory neurons and consequently affecting the sensory function. These defects were demonstrated to be dependent on the expression of Sema5b and Robo2. The expression of both proteins together could better overcome the defects caused by Mecp2 deficiency as compared to the expression of either Sema5b or Robo2 alone. Sema5b and Robo2 were downregulated upon Mecp2 silencing or in mecp2-null embryos, and Chromatin immunoprecipitation (ChIP) assay using antibody against Mecp2 was able to pull down specific regions of both Sema5b and Robo2 promoters, showing interaction between Mecp2 and the promoters of both genes. In addition, cell-specific expression of Mecp2 can overcome the innervation and sensory response defects in Mecp2 morphants indicating that these MeCP2-mediated defects are cell-autonomous. The sensory deficits caused by Mecp2 deficiency mirror the diminished sensory response observed in Rett syndrome patients. This suggests that zebrafish could be an unconventional but useful model for this disorder manifesting defects that are not easily studied in full using rodent models.

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Section: Resultsmentioning

confidence: 99%

Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2

Leong

Lim

Korzh

et al. 2015

Front. Cell. Neurosci.

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“…These defects were described during early postnatal development under standard in vivo housing conditions (Degano et al, 2009; Matarazzo et al, 2004; Palmer et al, 2008; Palmer et al, 2012). However, a major aspect of MeCP2 function is that it is regulated by synaptic activity (Chen et al, 2003; Martinowich et al, 2003; Zhou et al, 2006); the role of sensory activity in the consequences of MeCP2 deficiency during early postnatal stages, when sensory activity is critical, is unknown.…”

Section: Introductionmentioning

confidence: 99%

MeCP2 is required for activity-dependent refinement of olfactory circuits

Degano

Park

Judith

et al. 2014

Molecular and Cellular Neuroscience

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Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were used to produce physiological synaptic activity in gene-targeted mice in which specific olfactory circuits are visualized. Our results reveal defective postnatal refinement of olfactory circuits in Mecp2 knock out (KO) mice after sensory (odorant) stimulation. This failure in refinement was associated with deficits in the normal responses to odorants, including brain-derived neurotrophic factor (BDNF) production, as well as changes in adhesion molecules known to regulate axonal convergence. The defective refinement observed in Mecp2 KO mice was prevented by daily treatment with ampakine beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal stage might circumvent the detrimental effect of MeCP2 deficiency on circuitry maturation. The present results provide in vivo evidence in real time for the role of MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity.

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“…However, we need to take a cautious approach in interpreting the results, because the effects of MeCP2 null are mostly cell type- or tissue type-dependent. For example, while mitral cell dendrites developed normally in Mecp2 KO (Palmer et al 2012 ), pyramidal neurons in the motor cortex showed deficient arborization (Stuss et al 2012 ). Recent studies have shown that MeCP2 regulates the gene expression through binding to methylated DNA as well as various epigenetic modifications (Mellén et al 2012 ; Lee et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of MeCP2 causes subtle alteration in dendritic arborization of retinal ganglion cells

Lee

Mariappan

et al. 2021

Animal Cells and Systems

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Methyl-CpG-binding protein (MeCP2) is highly expressed in neurons. It plays an important role in the development of synapses and the formation of circuits in the central nervous system (CNS). Mutations in MECP2 cause neurodevelopmental disorders and mental retardation in humans. Therefore, it has become important to determine the distribution and function of MeCP2 in vivo. The retina consists of three nuclear cell layers and two layers of synapses; neurons in each layer are connected to form fine circuits necessary for visual signal transduction. Using immunohistochemical analysis, we found that MeCP2 was expressed in all nuclear cell layers, with differences in the levels of MeCP2 expression observed among the layers. To understand the structural defects in the retina due to the loss of MeCP2, we sought to elucidate the organization of the retinal structure in the Mecp2 knockout (KO) mouse. Overall, we found a normal retinal structure in Mecp2 KO mice. However, because Mecp2 mutations have a highly variable effect on neuronal architecture, we analyzed morphological changes in a subset of retinal ganglion cells of Mecp2 KO mice. In Thy1-GFP mice crossed with Mecp2 mutant mice, Sholl intersections analyses showed a subtle increase in number of intersections due to increased branching proximal to the soma in Mecp2 KO mice. Our results demonstrate that the expression of MeCP2 and the effects of Mecp2 mutations are highly specific to tissue and cell types.

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Normal mitral cell dendritic development in the setting of Mecp2 mutation

Cited by 7 publications

References 61 publications

Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2

Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2

MeCP2 is required for activity-dependent refinement of olfactory circuits

Loss of MeCP2 causes subtle alteration in dendritic arborization of retinal ganglion cells

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