Neurogenesis continues in the adult brain within an extensive germinal zone on the walls of the lateral ventricles called the Subventricular Zone (SVZ). SVZ astrocytes (B cells) function as adult neural stem cells (NSCs), generating transit amplifying C cells which give rise to neurons (Type A cells). New SVZ neurons migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) where they differentiate into multiple types of local interneurons. It remains unknown if B cells self-renew in vivo, how many times C cells divide before they generate new neurons, and whether generation of different neuronal lineages involves different patterns of proliferation for B and C cells.
Aim 1 will address these important gaps in our understanding of the SVZ. A recent study has redefined the architecture for the SVZ, revealing a pinwheel arrangement of B and ependymal cells and the apical-basal organization of B cells. The core of these pinwheels contains the apical compartments of B cells with primary cilia contacting the ventricle. Primary cilia concentrate essential components for Shh signal transduction and other pathways known to regulate B cell proliferation.
Aim 2 will explore the role of primary cilia in adult SVZ NSCs. SVZ astrocytes with NSC properties in vitro have also been identified in adult human brain, suggesting that SVZ adult NSCs could be used for therapeutic neuronal and glial replacement. However, the structure of the human SVZ is different from that in rodents. In addition, the extent of SVZ NSC proliferation in vivo and the ability of these cells to generate neurons that migrate long distances into the OB in adult humans remains highly controversial. This controversy is addressed by work proposed in Aim 3. Experiments in Aim 1 will investigate the cell cycle times of different SVZ progenitors, determine whether B cells self-renew in vivo and the number of times C cells divide before generation of different types of neurons in the rodent SVZ.
Aim 2 uses genetic methods to remove the primary cilia in adult rodent NSCs to investigate the role of this apical organelle in the proliferation of adult NSCs.
Aim 3 will determine the developmental origins of the unique organization of the adult human SVZ and will investigate age dependent changes in the levels of SVZ proliferation and possible fates of young neurons derived from the SVZ. We also intend to clarify whether an RMS exists in adult human brain and how this structure changes through development. Preliminary results suggest that: 1) B cells are consumed with age and their proliferation may be regionally regulated;2) primary cilia play a key role in the proliferation of adult NSCs;3) young neurons are present in the developing human SVZ, but interestingly very scarce along the olfactory track;4) a possible medial extension of the human RMS may exist. The above experiments will provide basic information on the most extensive germinal niche in the postnatal brain.
Neural Stem Cells (NSCs) that continually generate new neurons exist in the walls of the liquid filled cavities (ventricles) in the adult brain. This germinal region, called the subventricular zone (SVZ), is the largest single source of NSCs in the adult brain. In rodents, new neurons born in the SVZ migrate to the olfactory bulb, where they continually replace older neurons. The progenitor cells involved in adult neurogenesis in rodents have been identified, but we do not know how frequently they divide or the precise pattern of cell divisions and cell cycle length that leads to the generation of different types of neurons. Experiments proposed here will specifically determine the cell cycle time for adult SVZ progenitors and determine if cell cycle dynamics vary for different regions of the SVZ. The regulation of SVZ NSCs proliferation remains poorly understood. Recent work indicates that the NSCs contact the ventricle directly with a specialized extension called the primary cilium. Primary cilia are like cellular antennas that are receptive to external signals and multiple important growth factor receptors and signaling molecules are thought to be concentrated in primary cilia. We propose experiments to remove the primary cilium in adult NSCs and study the effects on the proliferation of adult NSCs. It remains controversial whether neurogenesis and long-range migration to the olfactory bulb, like those observed in adult rodents, occurs in adult humans. We propose to study how the SVZ develops in humans and to identify migratory routes and levels of proliferation at different ages. This information is essential to translate some of our observations in animal models to the clinic. This work will help in the development of novel strategies for brain repair and suggest how derailed proliferation of endogenous precursors might lead to tumor formation.
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