Title

Characterization of BMPs, noggin and their interactions in neocortical neurogenesis

Date of Completion

January 2000

Keywords

Biology, Molecular|Biology, Neuroscience|Biology, Cell

Degree

Ph.D.

Abstract

The majority of neurons that populate the mature cerebral cortex are generated from neuroepthelial. cells that surround the lateral ventricles of the embryonic brain. This process includes multiple steps, such as progenitor cell divisions, cell commitment, cell differentiation, and neuronal migration. During the past two decades, progress has been made in elucidating the mechanisms regulating neocortical neurogenesis. Bone morphogenetic proteins (BMPs) and noggin are two regulators involved in many events of embryogenesis and early neural induction; however, the expression patterns and functions of these two proteins in developing neocortex are not clear. This thesis presents a group of experiments demonstrating that BMPs and noggin play important roles in neocortical neurogenesis. I demonstrate that BMPs are present in the ventricular zone (VZ) and most concentrated at the VZ surface. BMPs trigger neuronal differentiation of precursors in the neocortical VZ, and the BMP signaling is essential for neuronal differentiation and migration out of the VZ. Noggin is expressed in radial glial cells, and inhibits neuronal differentiation. Noggin exerts its inhibitory effect by interfering with BMPs signaling. Furthermore, the interaction between BMPs and noggin is essential in regulating the number of neurons produced during neocortial neurogenesis as well as their migration. This study provides the first evidence that a specific signaling molecule is present at the VZ surface, acts directly on VZ progenitor cells, and is essential for neocortical neurogenesis. This study also characterizes the interactions between two opposing factors in neocortical neurogenesis, and shows how these interactions modulate neuronal differentiation and migration. In its entirety, this study enhances our understanding of the molecular mechanisms controlling neocortical neurogenesis. Information concerning the mechanisms of fetal neurogenesis may be used to study adult cortical neurogenesis, and may also provide us with insight to the possible causes of brain disorders. ^