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REST overexpression in mice causes deficits in spontaneous locomotion

This journal club meeting discusses the consequences of overexpressing repressor element 1 silencing transcriptional factor (REST) in mice, leading to deficits in spontaneous locomotion. REST, a chromatin modifying silencing factor, regulates many genes involved in normal development and diseases. Overexpression of REST has been implicated in various conditions such as Huntington's disease, Parkinson's disease, epilepsy, ischemia, and neuroblastoma.

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REST overexpression in mice causes deficits in spontaneous locomotion

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  1. REST overexpression in mice causes deficits in spontaneous locomotion Journal Club Meeting 1

  2. Repressor element 1 silencing transcriptional factor (REST) • Chromatin modifying silencing factor • Regulates many genes involved in normal development and disease states • Repressor of neurogenesis in embryonic development • Expressed in neural stem cells (NSC’s) and diminish when neurons mature

  3. Multiple mechanisms of REST overexpression • Overexpression blocks migration and neuronal differentiation • Implicated in HD,PD, epileptic seizures, ischemia, neuroblastoma, (colon cancer and small-cell carcinomas) • REST in HD: thought that mHTT protein fails to sequester REST in cytoplasm and allows it to accumulate in nucleus where it represses target genes • HTT interacting protein 1 (HTTIP1): directly activates REST gene transcription in HD model • Decreases in miR-9, which should downregulate REST, are seen in HD cortex

  4. Overexpression of REST in Parkinson’s disease • Less clear than findings between REST and PD • Higher REST levels associated with lowered expression of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF)

  5. Main Goals of Paper • Create a conditional REST overexpression knock-in mouse using human REST (hREST) gene • Determine role of REST • Determine relationship between REST and DRD2 gene • Examine behavioral measurements of locomotion as it relates to their mouse model

  6. Figure 1a & b

  7. Figure 1c & d

  8. Figure 2

  9. Figure 3

  10. Figure 4 X-axis key: Black = IgG control antibody Gray = anti-REST antibody

  11. Figure 5

  12. Figure 6

  13. Figure 7a & b

  14. Figure 7c & d

  15. Figure 7e

  16. Figure 8a

  17. Figure 8b

  18. Summary • Made new mouse model • Their hREST OE was embryonic lethal just like REST-KO mice in a previous study • REST is a neurogenesis repressor • REST represses Drd2 • REST negatively regulates spontaneous locomotion when overexpressed in Drd2 + cells • Drd2 expressed in striatal neurons

  19. Discussion • Future plans: • Test if D-hREST specifically in MSN’s, DA neurons, and/or cholinergic interneurons • Cognitive symptoms test • REST inhibitor therapy to ameliorate locomotion deficits: • Previously made REST, REST-VP16 recombinant. REST-VP16 binds DNA, opposes REST (activates targets)

  20. Methods: ChIP 1 3 2 4

  21. Methods: Open Field Assay

  22. Methods: Rotarod assay

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