The subventricular zone (SVZ) is the most extensive germinal region in the adult mammalian brain and contains the largest postnatal repository of neural progenitor cells (NPCs). These primary progenitors continue to generate new neurons and glial cells throughout life. Adult SVZ NPCs, frequently called adult neural stem cells, have been considered homogenous and multipotent. However, preliminary results in the laboratory indicate that adult NPCs are regionally specified generating specific types of neurons in different locations of the SVZ. The proposed work focuses on understanding this heterogeneity: 1) Generating a comprehensive fate map of NPCs in different regions of the postnatal SVZ. Preliminary observations hint to novel neurogenic domains and the postnatal production of novel neuronal types. The site of birth of different types of neurons formed in the postnatal SVZ and the developmental origin of SVZ regional specification will be investigated. 2) Studying how the anatomy of the SVZ varies regionally and how NPCs differ in gene and marker expression in different domains of the SVZ preliminary results suggest regionally regulated expression of transcription and growth factors. Heterotopic transplantation of regionally labeled NPCs will be used to determine if NPC potential is cell-autonomous or is determined by the niche environments preliminary evidence suggests that specification is cell autonomous. 3) Investigating how the postnatal ventricular wall is patterned. Whole mounts of the ventricular wall will be used to visualize ependymal cells and SVZ NPCs differentiation. Gradients of maturation of this germinal wall in relation to the regional specification of the SVZ and the molecular events that regulate the patterning and differentiation of this epithelium will be elucidated. This work is a continuation of research on the mechanisms of adult neurogenesis in the SVZ. Young neurons born in this germinal layer migrate rostrally into the olfactory bulb (OB) where they differentiate into several types of local interneurons. These new neurons originate from NPCs, identified as SVZ astrocytes (type B cells), that are distributed throughout the SVZ. In order to reach the OB, young neurons form an extensive network of chain migration pathways. The new preliminary data uncovers an unexpected level of spatial specification, and explains the need for such a complex network of migratory pathways: to collect neuronal progeny from regionally specified SVZ progenitors. Investigating how NPCs become spatially specified and how the SVZ is patterned during development is an important next step to explain adult neurogenesis. SVZ NPCs have been implicated in brain repair and tumor initiation. Therefore, a thorough understanding of SVZ patterning will help understand the development and therapeutic potential of this postnatal neural germinal niche. Public Health Relevance: Neural stem cells persist in the adult brain and offer new perspectives for the treatment of neurodegenerative diseases like multiple sclerosis, Parkinson's, epilepsy and stroke. These progenitor cells can generate neurons and glial cells and it has been assumed that they are homogeneous and multipotent. However, recent preliminary observations in our laboratory indicate that neural stem cells in the adult brain are heterogeneous and produce different types of neurons depending on their location within the adult germinal niche. Proposed work will reveal the different types produced, their location, gene profile and origin of these different primary progenitor cells. Understanding this heterogeneity is fundamental to any future attempt to use adult neural stem cells for brain repair.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD032116-17
Application #
8094305
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Nitkin, Ralph M
Project Start
1994-09-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
17
Fiscal Year
2011
Total Cost
$437,408
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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