TRANSCRIPTIONAL REGULATION OF NEURONAL MIGRATION AND CELL FATE SPECIFICATION IN THE NEOCORTEX
Creators: name: Adnani, Lata
Publisher: name: Graduate Studies
Year: 2017
Subjects: subject: Biology--Cell
subject: Genetics
subject: FOS: Biological sciences
subject: Biology--Molecular
subject: Neuroscience
subject: Oncology
subject: Biochemistry
subject: Neocortex
subject: neurons
subject: migration
subject: Zac1
subject: Plag1
subject: Plagl2
subject: patterning
subject: oligodendroglioma
subject: Extracellular vesicles
subject: tumor-neural
subject: tumor-tumor
subject: EGF

description: The 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.