A mouse model with a mutation in the Mecp2 gene exhibits neurological symptoms similar to Rett syndrome (RTT), an X-linked neurodevelopmental disorder in females. Mecp2 encodes a protein that binds to methylated DNA and regulates gene silencing. Previous attempts to generate Mecp2-null mice failed due to embryonic lethality, but this study successfully created Mecp2-null mice using Cre-loxP technology. These mice showed severe neurological symptoms, including loss of movement, irregular breathing, and reduced weight, around six weeks of age. Heterozygous females also developed behavioral symptoms later. The delayed onset of symptoms in both mice and humans suggests that brain function stability, rather than development, is affected by Mecp2 loss. Mecp2-null mice were generated by deleting exons 3 and 4 of the Mecp2 gene in embryonic stem cells, followed by Cre-mediated deletion in brain tissue. The resulting mice showed severe neurological symptoms, with no detectable Mecp2 mRNA or protein. The phenotype was similar in mice with extensive brain-specific Mecp2 deletion, indicating that neuronal and glial cells are primarily affected. Mecp2-null males showed no initial symptoms but developed gait abnormalities and reduced movement. Mecp2-null females exhibited delayed onset of symptoms, including hindlimb clasping and breathing irregularities. The study also found that Mecp2-null mice had reduced body weight, which varied depending on genetic background. This suggests the presence of modifier genes influencing body weight. The results indicate that Mecp2 is essential for brain function, and its absence leads to neurological dysfunction. However, Mbd2, a related protein, can partially compensate for Mecp2 loss in some tissues. Despite this, Mecp2 appears to play a minimal role in methyl-CpG-dependent repression in fibroblasts. The findings support the idea that RTT is primarily a neurological disorder, with Mecp2 mutations causing functional instability in brain cells rather than developmental defects. The study provides a valuable model for understanding RTT and highlights the importance of Mecp2 in maintaining brain function.A mouse model with a mutation in the Mecp2 gene exhibits neurological symptoms similar to Rett syndrome (RTT), an X-linked neurodevelopmental disorder in females. Mecp2 encodes a protein that binds to methylated DNA and regulates gene silencing. Previous attempts to generate Mecp2-null mice failed due to embryonic lethality, but this study successfully created Mecp2-null mice using Cre-loxP technology. These mice showed severe neurological symptoms, including loss of movement, irregular breathing, and reduced weight, around six weeks of age. Heterozygous females also developed behavioral symptoms later. The delayed onset of symptoms in both mice and humans suggests that brain function stability, rather than development, is affected by Mecp2 loss. Mecp2-null mice were generated by deleting exons 3 and 4 of the Mecp2 gene in embryonic stem cells, followed by Cre-mediated deletion in brain tissue. The resulting mice showed severe neurological symptoms, with no detectable Mecp2 mRNA or protein. The phenotype was similar in mice with extensive brain-specific Mecp2 deletion, indicating that neuronal and glial cells are primarily affected. Mecp2-null males showed no initial symptoms but developed gait abnormalities and reduced movement. Mecp2-null females exhibited delayed onset of symptoms, including hindlimb clasping and breathing irregularities. The study also found that Mecp2-null mice had reduced body weight, which varied depending on genetic background. This suggests the presence of modifier genes influencing body weight. The results indicate that Mecp2 is essential for brain function, and its absence leads to neurological dysfunction. However, Mbd2, a related protein, can partially compensate for Mecp2 loss in some tissues. Despite this, Mecp2 appears to play a minimal role in methyl-CpG-dependent repression in fibroblasts. The findings support the idea that RTT is primarily a neurological disorder, with Mecp2 mutations causing functional instability in brain cells rather than developmental defects. The study provides a valuable model for understanding RTT and highlights the importance of Mecp2 in maintaining brain function.