Biology subjects

Merritt, J. K.

Publications and source records attributed to Merritt, J. K..

2 recordsLinked to original sources

bioRxiv2025

In vitro cellular phenotypes of cortical neurons from R255X MECP2 knock-in mice are improved by either expression of wildtype MeCP2 or read-through with G418

Approximately 60% of individuals with Rett syndrome (RTT) carry a nonsense variant in the MECP2 gene; thus, there is an unmet need to identify novel nonsense suppression compound(s) that can restore full length MeCP2 protein levels and function. Here, we characterized neuronal phenotypes in cultured cortical neurons from newborn knock-in mice harboring the MECP2 R255X variant. After 2 weeks in vitro, R255X mutant neurons showed smaller cell bodies, shorter dendrites, fewer dendritic branches, and a lower density of excitatory synapses when compared to wildtype (WT) neurons. Transduction of AAV9-MeCP2-GFP in R255X mutant neurons made these cellular phenotypes similar to those in WT neurons, including soma size, dendritic length and branching, and excitatory synapse density. As proof of principle for the potential clinical use of read-through compounds, cultured R255X mutant neurons treated with the aminoglycoside G418 for 72h in vitro showed cell body size and excitatory synapse density similar to WT neurons. We expect these combined approaches will identify effective compounds to suppress translation termination at a premature termination codon, which can be moved to further preclinical functional and behavioral studies in R255X MECP2 knock-in mice. Summary StatementExpression of wildtype MECP2 or treatment with G418 in vitro restored cell body size, dendritic length, and dendritic spine density in cortical neurons from R255X MECP2 knock-in mice to levels comparable to wildtype neurons.

neuroscience↗

bioRxiv2022

Behavioral and imaging analysis of Foxg1 heterozygous mice

FOXG1 Syndrome (FS) is a devastating neurodevelopmental disorder that is caused by a heterozygous loss-of-function (LOF) mutation of the FOXG1 gene, which encodes a transcriptional regulator important for telencephalic brain development. People with FS have marked developmental delays, impaired ambulation, movement disorders, seizures, and behavior abnormalities including autistic features. Current therapeutic approaches are entirely symptomatic, however the ability to rescue phenotypes in mouse models of other genetic neurodevelopmental disorders such as Rett syndrome, Angelman syndrome, and Phelan-McDermid syndrome by postnatal expression of gene products has led to hope that similar approaches could help modify the disease course in other neurodevelopmental disorders such as FS. While FoxG1 protein function plays a critical role in embryonic brain development, the ongoing adult expression of FoxG1 and behavioral phenotypes that present when FoxG1 function is removed postnatally provides support for opportunity for improvement with postnatal treatment. Here we generated a new mouse allele of Foxg1 that disrupts protein expression and characterized the behavioral and structural brain phenotypes in heterozygous mutant animals. These mutant animals display changes in locomotor behavior, gait, anxiety, social interaction, aggression, and learning and memory compared to littermate controls. Additionally, they have structural brain abnormalities reminiscent of people with FS. This information provides the framework for future studies to evaluate the potential for post-natal expression of FoxG1 to modify the disease course in this severe neurodevelopmental disorder.

neuroscience↗