Molecular Mechanisms Regulating Mammalian Forebrain Development

• Main Author: Tsui, David Chun Cheong
• Other Authors: Miller, Freda
• Language: en_ca
• Published: 2013
• Subjects: cortex; neurogensis; interneurons; Molecular
• Online Access: http://hdl.handle.net/1807/43741

While the extrinsic factors regulating neurogenesis in the developing forebrain have been widely studied, the mechanisms downstream of the various signaling pathways are relatively ill-defined. In particular, we focused on proteins that have been implicated in cognitive dysfunction. Here, we ask what role two cell intrinsic factors play in the development of two different neurogenic compartments in the forebrain. In the first part of the thesis, the transcription factor FoxP2, which is mutated in individuals who have specific language deficits, was identified to regulate neurogenesis in the developing cortex, in part by regulating the transition from the radial precursors to the transit amplifying intermediate progenitors. Moreover, we found that ectopic expression of the human homologue of the protein promotes neurogenesis in the murine cortex, thereby acting as a gain-of-function isoform. In the second part of the thesis, the histone acetyltransferase CREB-binding protein (CBP) was identified as regulating the generation of neurons from medial ganglionic eminence precursors, similar to its role in the developing cortex. But CBP also plays a more substantial role in the expression of late interneuron markers, suggesting that it is continuously required for the various stages of neurogenesis at least in the ventral neurogenic niche. Finally, similar to cortical precursors, the function of CBP in the ventral forebrain precursors is also dependent on histone acetylation. Together, these studies shed light on some of the key intrinsic players that regulate the differentiation of neural precursors in the embryonic murine forebrain, and they also suggest potential mechanisms for the pathogenesis of various cognitive dysfunctions.