TRANSCRIPTIONAL REGULATION OF NEURONAL MIGRATION AND CELL FATE SPECIFICATION IN THE NEOCORTEX

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atmire.migration.oldid5814
dc.contributor.advisorSchuurmans, Carol
dc.contributor.advisorChan, Jennifer
dc.contributor.authorAdnani, Lata
dc.contributor.committeememberChilds, Sarah
dc.contributor.committeememberKurrasch, Deborah
dc.contributor.committeememberWhelan, Patrick
dc.contributor.committeememberHolmberg, Johan
dc.date.accessioned2017-07-21T19:13:29Z
dc.date.available2017-07-21T19:13:29Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractThe events that lead to the generation of a functional neocortex are tightly regulated and require the coordination of multiple events, including progenitor proliferation and maturation, neuronal differentiation and neuronal migration. I began my PhD studies by investigating the role of the zinc finger gene Zac1 in neocortical development. Zac1 was initially identified in the Schuurmans’ lab in a subtractive screen designed to isolate downstream effectors of the proneural gene Neurog2, which is a critical regulator of neocortical development. Previous studies had identified a role for Zac1 in the developing retina and cerebellum. I hypothesized that Zac1 would have essential roles in regulating the key events during the development of a functional neocortex. We tested the sufficiency of Zac1 in progenitor cell proliferation, progenitor cell maturation, neuronal differentiation and neuronal differentiation. We have demonstrated that Zac1 functions in regulating the radial glial cell to intermediate neuronal precurssor transition, neuronal differentiation and neuronal migration in the embryonic neocortex, acting in part through the regulation of Pac1 (Chapter 2). In the next stage of my PhD project, I tested the requirement and sufficiency of of two other members of the Plag family of transcription factors, Plag1 and Plagl2 in the developing neocortex (Chapter 3). Previously, it was established that Plag1 and Plagl2 (as well as Zac1) are associated with intrauterine growth restriction (IUGR) and intellectual disabilities. I found that Plag1 and Plagl2 have complementary roles in maintaining the ventral and dorsal boundaries of gene expression in the developing telencephalon, respectively, and that Plag1 is required while Plagl2 is sufficient to induce neocortical progenitor proliferation. Finally, in Chapter 4, I switched gears and focused my study on a disease of the neocortex, which is oligodendroglioma (ODG). My goal was to elucidate how ODG cells influence the behavior of mouse neural stem cells (mNSCs), and I hypothesized that the communication between ODG cells and mNSCs was , in part, EV dependent. I was able to show that ODG cells secrete factors that have dosage-specific effects on the growth of normal neural cells. In particular I demonstrated that ODG cells communicate with mNSCs by secreting EVs that carry several signaling molecules as cargo, including EGF, which acts in a dose-dependent manner to influence mNSC proliferation. I also demonstrated that inhibition of EV secretion by blocking the nSMase pathway increases ODG ‘tumoursphere’ number and size, while ectopic expression of this pathway lead to decrease in the generation of ‘tumour sphere’. Taken together, through my PhD work new molecular insights into how neocortical development is regulated have been gained, and an onset to understanding one of the means of a disease to influence the behavior of mNSCs in a non-cell autonomous manner have been studied. These studies bring us closer to understanding the molecular mechanisms that underlie normal neocortical development, and possibly open up new avenues for testing various biomarkers and therapies for ODG.en_US
dc.identifier.citationAdnani, L. (2017). TRANSCRIPTIONAL REGULATION OF NEURONAL MIGRATION AND CELL FATE SPECIFICATION IN THE NEOCORTEX (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28505en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/28505
dc.identifier.urihttp://hdl.handle.net/11023/3979
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectGenetics
dc.subjectBiology--Molecular
dc.subjectNeuroscience
dc.subjectOncology
dc.subjectBiochemistry
dc.subject.otherNeocortex
dc.subject.otherneurons
dc.subject.othermigration
dc.subject.otherZac1
dc.subject.otherPlag1
dc.subject.otherPlagl2
dc.subject.otherpatterning
dc.subject.otheroligodendroglioma
dc.subject.otherExtracellular vesicles
dc.subject.othertumor-neural
dc.subject.othertumor-tumor
dc.subject.otherEGF
dc.titleTRANSCRIPTIONAL REGULATION OF NEURONAL MIGRATION AND CELL FATE SPECIFICATION IN THE NEOCORTEX
dc.typedoctoral thesis
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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