Student Theses and Dissertations

Daniel A. Lim

Date of Award

2000

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Alvarez-Buylla Laboratory

Abstract

Neurogenesis persists in restricted regions of the adult vertebrate brain. The largest region of adult neurogenesis is the subventricular zone (SVZ) of the lateral ventricle wall. Neural stem cells reside in the SVZ. The S V Z cell types and molecular signals necessary for this neurogenic niche were poorly understood. Here, I first demonstrate that astrocyte-like cells in the SVZ (type B cells) can self-renew and differentiate into mature brain cells. This data contributed to the identification of type B cells as the S V Z stem cell. In vivo, all S V Z cell types are in direct contact with type B cells. By reconstituting cell-cell interactions of dissociated SVZ cells in culture, I defined an in vitro cellular environment that recapitulates SVZ neurogenesis; these cultures provided an in vitro assay for the study of external molecular signals that regulate S V Z neurogenesis. Ependymal cells lie adjacent to the SVZ. I show that the bone morphogenetic protein (BMP) antagonist Noggin is expressed by ependymal cells and that S V Z cells express B M P s as well as their receptors. In vitro, B M P signaling potently inhibited neurogenesis. Conversely, Noggin protein in vitro promoted neurogenesis. Overexpression of BMPs in ependymal cells decreased SVZ cell proliferation and abolished type A cell regeneration. Ectopic Noggin expression in the normally nonneurogenic striatum promoted neuronal differentiation of transplanted S V Z cells. I thus propose that ependymal Noggin production creates a neurogenic niche in the adjacent SVZ by antagonizing B M P signaling. To identify other genes with roles in the SVZ, I utilized high-density oligonucleotide arrays to determine the transcriptional profiles of the S V Z region as well as purified type B and ependymal cells. SVZ regional and cell-specific expression profiles were compared to those of other brain regions. Differential gene expression was validated by Northern blot and histological techniques. This transcriptional profile data provides new markers and candidate regulatory genes for future investigations into the SVZ neurogenic niche.

Comments

A thesis submitted to the faculty of Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

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