Home
Resource
The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex
PDF
PDF format is widely accepted and good for printing.
Plug-in required
PDF-1(3.26 MB)
Citation & Export
View Usage Statistics
Staff View

Citation & Export
Hide

Simple citation

Zucco, Avery. The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex. Retrieved from https://doi.org/doi:10.7282/t3-9ahy-yx47

Export

Click here for information about Citation Management Tools at Rutgers.

Statistics
Hide

Description

TitleThe generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex
NameZucco, Avery (author); D'Arcangelo, Gabriella (chair); Hart, Ronald (internal member); Dreyfus, Cheryl (internal member); Roko-Rasin, Mladen (internal member); Jacinto, Estella (outside member); Rutgers University; School of Graduate Studies
Date Created2018
Other Date2018-10 (degree)
SubjectNeuroscience, Tuberous sclerosis
Extent1 online resource (140 pages : illustrations)
DescriptionTuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by the mutation of either the TSC1 or TSC2 genes and characterized by the presence of benign cortical lesions known as cortical tubers. A large proportion of patients with TSC exhibit neurological symptoms including epilepsy and intellectual disability, and a further 50% meet the diagnostic criteria for Autism. However, the appearance of this broad spectrum of neurologic manifestations does not always correlate with the neuroanatomical defects common to TSC, suggesting the possibility of underlying functional defects affecting neural development in TSC patients. Here we have utilized neural progenitor cells (NPCs) capable of fully differentiating into neurons, which carry a heterozygous TSC2 mutation generated from patient-derived induced pluripotent stem cells (iPSCs) to investigate TSC cellular and molecular phenotypes. In these cell lines we observe that TSC2 +/ NPCs exhibit changes in cell signaling along the Akt/mTORC1 signaling axis. This pathway is classically affected in TSC, with elevated pS6 and decreased phospho-Akt levels known as neuropathological hallmarks in knockout mouse models and studies of abnormal human tissue. Consistent with these previous findings we observed a decrease in the activity of AKT as measured by levels of phospho-AKT Thr308 and Ser473. Evidence of increased mTORC1 signaling was seen in one patient, but not another, suggesting TSC2 heterozygosity may produce modest signaling changes near a functional threshold for generating a molecular phenotype in NPCs. TSC2 heterozygous NPCs also exhibited a reduced capacity to produce neurons in vitro, suggesting that neural development may be impacted in TSC. Moreover, this phenotype was reproduced upon AKT inhibition of control NPC lines, but was unaffected under treatment with rapamycin, suggesting that AKT signaling may play a more prominent role in mediating the neurodevelopmental defects of TSC than previously thought.
NotePh.D.
NoteIncludes bibliographical references
Noteby Avery Zucco
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-9ahy-yx47
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
Version 8.5.5
Rutgers University Libraries - Copyright ©2024