Date of Award

Summer 8-27-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Advisor(s)

MacDonald, Jessica L.

Keywords

Cortical development, Mecp2, Neurological disorders, NF-KB pathway, Rett syndrome, Vitamin D

Subject Categories

Cell and Developmental Biology | Developmental Biology | Genetics and Genomics | Life Sciences | Neuroscience and Neurobiology

Abstract

Rett syndrome (RTT) is a progressive and severe X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. There is currently no effective treatment for RTT. Female RTT patients develop relatively normally during the first 6-18 months of life, after which they undergo a period of rapid regression, losing the ability to talk, walk and purposefully use their hands, in addition to suffering from deceleration of head growth, and onset of repetitive, autistic behaviors. RTT symptoms can be partially reversed by the re-expression of Mecp2 in adult mice, suggesting the potential for post-symptomatic therapeutic intervention. Among the many dysfunctions caused by the loss of Mecp2 is aberrant NF-kB signaling. Importantly, genetically attenuating NF-kB rescues some characteristic neuronal phenotypes of RTT. Given that vitamin D (VitD) inhibits NF-kB activity and VitD deficiency is prevalent in RTT patients, the focus of this dissertation was to investigate whether VitD supplementation would ameliorate the many Mecp2-null phenotypes in RTT mouse models. Using an in vitro approach, I determined that adding the activated form of vitamin D to Mecp2-knockdown cortical neurons reduces the aberrant NF-kB activation and promotes neurite outgrowth. Further, VitD dietary supplementation moderately extends the lifespan of Mecp2-null mice and rescues dendritic complexity and soma area of 8-week-old Mecp2-null and 5-month-old heterozygous female mice in a dose dependent manner. RNA-sequencing analyses indicate that VitD supplementation normalizes the expression of many differentially expressed genes associated with neuronal morphology in the cortex of Mecp2 heterozygous female mice at 7 months of age. Moreover, I demonstrate that VitD supplementation improves motor deficits and anxiety-like behavior of RTT female mice, in an age dependent manner. Interestingly, I have found that insufficient serum 25(OH)D concentration, the major circulating form of vitamin D, only disrupts the behavior of Mecp2 deficient mice, not altering the performance of their wild-type littermates. Additionally, exposure to VitD deficient chow does not exacerbate behavioral outcomes of Mecp2 heterozygous female mice broadly, even though it leads to extensive transcriptome alterations. Both VitD supplementation and restriction diets result in altered expression of genes involved in the metabolism of VitD. This is observed exclusively in Mecp2 mutant mice, suggesting that the loss of Mecp2 increases susceptibility to VitD homeostasis disruptions in mice. Overall, my data demonstrate that VitD supplementation ameliorates phenotypes of Mecp2 mutant mice and its modulation could underlie RTT pathology. Moreover, my transcriptome data provides novel insight and opens up new exciting avenues for investigation.

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Open Access

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