Defining the Role of Proneural Genes in Neurogenesis, Specification, and Migration of Mouse VMH Neurons
Date
2020-01
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
The ventromedial hypothalamus (VMH) is a hypothalamic nucleus important for controlling satiety and reproductive behaviors, among other physiologies. Despite these important roles, the genetic programs driving VMH development are just starting to be explored. Since proneural genes are one of the key drivers of neurodevelopment throughout the brain, we asked whether the proneural genes Achaete-scute homolog 1 (Ascl1) and Neurogenin 2 (Neurog2) play key roles in VMH development, given their expression in VMH progenitors. My hypothesis is that proneural genes play a role in neurogenesis, cell fate decisions and/or in the migration of VMH neurons. To start, I investigated the role of Ascl1 in the specification and fate of VMH neurons. I showed that Ascl1+ lineages give rise to a large population of VMH neurons and that Ascl1 is necessary for promoting VMHDM and VMHC neuronal specification. In addition, my results revealed that Ascl1 played an important role in the timing of neurogenesis within the tuberal hypothalamus. Next, I examined the role of Neurog2 in the neurogenesis of VMH specific neurons and showed that Neurog2 was necessary for timely cell cycle exit and birth of VMH neurons. Moreover, I showed Neurog2 was required for proper development of the VMH at both early and late embryonic developmental stages. Neurog2 is particularly important for proper differentiation of VMHVL neurons. Finally, I studied the role of Ascl1 and Neurog2 in cell sorting within the maturing VMH. My results revealed that between E15.5 to E17.5 and in the absence of either Ascl1 or Neurog2, there is a change in the final positioning of cells. Since Ascl1 and Neurog2 can act through Rnd3 and Rnd2 proteins to regulate cortical neuronal migration, I asked whether Ascl1 and Neurog2 potentially employ a similar mechanism to regulate VMH cell sorting. My results showed both Rnd2 and Rnd3 were expressed within the VMH nucleus across VMH embryonic developmental stages. In addition, at later stages such as E15.5 and E19.5, the expression of both Rnd2 and Rnd3 was significantly decreased in the absence of Neurog2 and Ascl1 respectively. Finally, using a live cell imaging technique, I assayed neuronal movement during cell sorting events within the VMH. Together, these studies provide insight into the varying roles proneural genes play in the developing tuberal hypothalamus.
Description
Keywords
VMH, proneural genes, development, cell fate decision, neurogenesis, cell sorting
Citation
Aslan Pour Kal Bolandi, S. (2020). Defining the role of proneural genes in neurogenesis, specification, and migration of mouse VMH neurons (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.