Development of the central nervous system requires the coordinated interplay of intrinsic and extrinsic factors. I examined the actions of an extrinsic factor, TWEAK, and an intrinsic factor, Iroquois1 (Irx1) on neural progenitor cell behavior. Embryonic day 12 (E12) and post-natal day 1 (PN1) neural progenitor cells both express Fn14, the receptor for TWEAK, but they respond differently to TWEAK treatment. TWEAK treatment did not alter the proliferation of E12 neural progenitor cells, but it shifted PN1 progenitor cells towards cell cycle phases G0 and G1 and reduced their rate of CldU incorporation. Conversely, TWEAK induced extensive neurite outgrowth by the neuronal progeny of E12 but not PN1 progenitors. These studies indicate that TWEAK signaling and Fn14 receptor activation exert different effects on neural progenitor cells and their progeny depending upon the developmental stage of the cells. For my second project, I focused on the function of patterning factors Irx1 and Pre-B Cell Leukemia Transcription Factor 1 (Pbx1) in lineage commitment of neural progenitor cells. We established that Irx1 is a BMP4-repressed patterning gene whose function is regulated by the MAPK signaling pathway. Irx1 over-expression suppresses progenitor cell proliferation and commitment to an astrocyte fate in a manner that is dependent upon binding to Pbx1. Both Irx1 and Pbx1 also bind to Dlx1, Dlx2 and Dlx5, and this interaction facilitates the activation of a Dlx-responsive enhancer element by Dlx2. These findings demonstrate that Pbx1 and Irx1 play important roles in the process of lineage commitment by neural progenitor cells.

Last modified

• 08/06/2018

Creator

• Caitlin Ariel Hamill

DOI

• https://doi.org/10.21985/N2Q425

Subject

• Neuroscience Institute Graduate Program

Keyword

• CNS development
• Iroquois
• TWEAK

Date created

• 2007-07-17

Resource type

• Dissertation

Rights statement

• In Copyright