Ribeiro MC, Moore SM, Kishi N, Macklis JD, MacDonald JL. 2020. Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in Mutant Mice. eNeuro. 7(3). Pubmed: 32393583 DOI:10.1523/ENEURO.0167-20.2020


Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator We previously identified aberrant NF-κB pathway upregulation in brains of -null mice and demonstrated that genetically attenuating NF-κB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-κB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-κB pathway inhibitor vitamin D ameliorates neuronal phenotypes in -mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that -null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of knock-down cortical neurons Further, dietary supplementation with vitamin D in early symptomatic male hemizygous null and female heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of -nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-κB pathway inhibition might be a therapeutic target for RTT.
Copyright © 2020 Ribeiro et al.

Related Faculty

Photo of Jeffrey D. Macklis

Jeffrey Macklis investigates molecular controls and mechanisms over neuron subtype specification, development, diversity, axon guidance-circuit formation, and pathology in the cerebral cortex. His lab seeks to apply developmental controls toward brain and spinal cord regeneration and directed differentiation for in vitro mechanistic modeling using human assembloids.

Search Menu