Proneural Genes in Neocortical Development
| atmire.migration.oldid | 1667 | |
| dc.contributor.advisor | Schuurmans, Carol | |
| dc.contributor.author | Li, Saiqun | |
| dc.date.accessioned | 2013-12-09T18:32:53Z | |
| dc.date.available | 2014-03-15T07:00:16Z | |
| dc.date.issued | 2013-12-09 | |
| dc.date.submitted | 2013 | en |
| dc.description.abstract | The timing of neocortical development is regulated by both intrinsic proneural genes Neurog2 and Ascl1, and extrinsic signals. However, how these intrinsic factors and extrinsic signals coordinatedly control neural cell fate decisions was not well understood at the start of my studies. Neurog2 and Ascl1 were known to be expressed by dorsal and ventral telencephalic progenitors, respectively. In the embryonic dorsal telencephalon, Neurog2 was known to promote the differentiation of glutamatergic projection neurons, while in the ventral telencephalon, Ascl1 was known to promote the formation of GABAergic interneurons and oligodendrocyte precursor cells (OPCs). However, little was understood about the regulatory controls that governed Neurog2 and Asc11’s proneural activities. During my PhD study, I first found that the proneural activity of Neurog2 declined at later stages of cortical neurogenesis, which was controlled by a simultaneous increase in GSK3 activity (Chapter 3). Furthermore I found that GSK3 inhibited Neurog2’s proneural activity through direct phosphorylation, which altered Neurog2-cofactor interactions. Next, I found that RAS/ERK signaling controlled a Neurog2-Ascl1 genetic switch, promoting Ascl1 expression while inhibiting Neurog2 expression (Chapter 4). Moreover, I found that RAS/ERK signaling modified Ascl1’s functions through direct phosphorylation, with higher levels of RAS/ERK causing Ascl1 to select OPC differentiation pathways, while lower levels allowed Ascl1 to promote a GABAergic neuronal fate. Notably, the interaction between RAS/ERK signaling and Ascl1 was found to be important in both normal neocortical development and in gliomagenesis. Finally, I observed that Neurog2 and Ascl1 proteins were co-expressed in a subset of early cortical progenitors, with the frequency of co-expression declining over developmental time (Chapter 5). Furthermore, I found that the Neurog2-Ascl1 co-expression is associated with enhanced neural stem cell properties and a decreased propensity to undergo neuronal differentiation. Accordingly, in Neurog2-/-;Ascl1-/- double mutant cortices, I found that neurogenesis and laminar marker expression was accelerated. I thus conclude that the Neurog2-Ascl1 co-expression ‘primes’ a subset of cortical progenitors to prevent lineage selection until later in development. Taken together, I made a great deal of progress in improving our understanding of how the proneural genes cooperate with extrinsic signals to regulate the timing of neocortical development. | en_US |
| dc.identifier.citation | Li, S. (2013). Proneural Genes in Neocortical Development (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27459 | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/27459 | |
| dc.identifier.uri | http://hdl.handle.net/11023/1186 | |
| dc.language.iso | eng | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | en |
| dc.publisher.place | Calgary | en |
| dc.rights | University 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.subject | Neuroscience | |
| dc.subject.classification | Proneural genes | en_US |
| dc.subject.classification | Neocortical development | en_US |
| dc.subject.classification | Neurog2 | en_US |
| dc.subject.classification | Ascl1 | en_US |
| dc.subject.classification | GSK3 | en_US |
| dc.subject.classification | RAS/ERK signaling | en_US |
| dc.title | Proneural Genes in Neocortical Development | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Neuroscience | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.item.requestcopy | true |