Date of Award

8-2004

Level of Access

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Joseph M. Verdi

Second Committee Member

Doug B. Spicer

Third Committee Member

Robert E. Friesel

Abstract

The development of the central nervous system requires the orchestration of numerous instructive and permissive cues. These factors are secreted from signaling centers and function in a concentration dependent manner that effects the proliferation, survival and differentiation of neural progenitors (NP) and their differentiated progeny. The family including bone morphogenetic proteins (BMPs) are key regulators of NP expansion and survival. However, once NP become committed to a neuronal fate and begin to differentiate they compete for limited amounts of neurotrophin that facilitate further growth and survival. Here we show that the p75 neurotrophin receptor interacting protein NRAGE is expressed in NP of the developing cortex during the peak period of progenitor apoptosis. This NRAGE dependent apoptosis of NP cells is mediated through the BMP TAKITABI- XIAP signaling complex leading to the activation of p38. The combined BMP activation of p38 and Smad signaling adversely effects the terminal differentiation of NPs into neurons. These results demonstrate the conserved nature of progenitor and trophic dependent apoptosis through the utilization of NRAGE and common cell death machinery highlighting the important mulitfunctionality of NRAGE during neurogenesis.

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