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Title: Investigating a Mechanism for Cereblon as the Primary Mediator of Thalidomide-induced Teratogenicity through Ciona Intestinalis
Authors: Williams, Yezekiel
Advisors: Levine, Michael
Department: Molecular Biology
Class Year: 2021
Abstract: Thalidomide, notoriously prescribed as a treatment for morning sickness, has been discovered to be effective at treating a range of various illnesses and immune conditions. However, shortly after its development, it was revealed to produce limb deformities in infants when administered during pregnancy. Notwithstanding this discovery, understanding the mechanism behind these defects could facilitate the production of beneficial immunomodulatory treatments without causing embryopathy. Investigating how thalidomide induces limb deformity, as studied in a member of the closest relative species to early vertebrates, Ciona intestinalis, may also deepen our understanding of vertebrate limb development. The primary target of thalidomide, CRBN, recruits zinc finger transcription factors and other proteins for degradation. Single cell RNA sequencing in Ciona progenitor cells produced an array of genes involved in several components of muscle and heart development or function (cytoskeletal regulation, the ECM, cell signaling, E3 ligase activity) that were upregulated upon Crbn overexpression. Binding motifs for previously identified regulators of Ciona heart and tail muscle identity were investigated in the regulatory sequences of the genes affected by Crbn overexpression. This study concludes that Myc, Otx, Snail, Twist, Usf, and/or Zeb, which are likely targeted by Crbn for proteasomal degradation, may repress Mnx1, Ets2, and/or MyoD, the putative activating transcription factors, leading to the transcription of myogenic genes. The putative repressors in the presented model are not determined to be direct substrates of Crbn activity by this study and their degradation and downstream regulatory effects in progenitor cells require further experimental confirmation.
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Molecular Biology, 1954-2021

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