During embryonic development neurons of the cerebral cortex are generated from various progenitor cells that have progressively restricted fate. Understanding the multiple regulatory pathways that regulate the cell cycle kinetics and the identity of neurons is crucial to comprehend the etiology of severe developmental defects such as microcephaly and polymicrogyria and also the evolutionary expansion of the mammalian cerebral cortex. Intermediate progenitors (IPCs) express the transcription factor Tbr2 (a T-box gene) and deletion of this gene causes a decrease in brain size and cortical thickness. However, little is known about the molecular mechanisms regulating behavior of IPCs. In this thesis, I studied the molecular mechanisms regulating cell division and cell fate choices in IPCs using an overexpression system. I show that Tbr2 controls the expression of key genes such as Cdk4, Aspm and Wnt5a by directly binding to upstream regulatory sequences. These downstream targets could explain the role played by Tbr2 in cell cycle, spindle assembly and Wnt signaling in intermediate progenitors. The interaction with Aspm also suggests a possible mechanism of self-renewal of IPCs leading to an expanded generation of cortical neurons and ultimately an increased cortical size. While the role of IPCs in cortical neurogenesis is undisputed, it is widely believed that they contribute only towards supragranular layers. Using a knock-in transgenic mouse line (Tbr2<sup>Cre</sup>), I show that IPCs provide glutamatergic neurons (but not GABAergic neurons or GFAP+ astrocytes) towards all cortical layers in a significant proportion (20-40%). I also show that clonally generated neurons disperse within tangential dimension across the cortex significantly closer (142.1 ± 76.8 µm) than unrelated ones (294.9 ± 105.4 µm) though within the confines of a cortical column (300-600 µm). Finally, I describe the similarity in the germinal zones of a large-brained gyrencephalic rodent, agouti and a lissencephalic primate, marmoset. Both these species show similar germinal zone cytoarchitecture and distribution of various progenitors. Further, the number of IPCs is grossly expanded thus demonstrating the conserved role of IPCs in cortical expansion regardless of the folding status of the cortex in these two species.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:604452 |
| Date | January 2013 |
| Creators | Vasistha, Navneet A. |
| Contributors | Molnár, Zoltán |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:cca66b37-145e-4212-ab01-0f11fe1c9be5 |
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