Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms of NSC neurogenesis and gliogenesis is key to unlocking their therapeutic potential. NSC fate is controlled by the collective action of many genes expressed in parallel, and chromatin remodeling is an epigenetic mechanism that coordinates the activation and repression of sets of genes. This proposal focuses on Mll (Mixed lineage leukemia), a chromatin remodeling factor related to Drosophila Trithorax. The trithorax group (trxG) and Polycomb (PcG) gene products are part of an evolutionarily conserved chromatin remodeling system that selectively maintain and silence gene expression, respectively. PcG member Bmi1 is required for NSC self-renewal;roles for trxG member Mll in neural development are unknown. Our Preliminary Studies indicate that Mll-deficient NSCs in the postnatal brain subventricular zone (SVZ) can survive, proliferate, and efficiently differentiate into glial lineages;however, neuronal differentiation is severely impaired. Thus, Mll appears to maintain a transcriptional program that specifically instructs neurogenesis and not gliogenesis. We hypothesize that Mll is broadly required in neural development for specific neuronal lineages. To test this hypothesis and to define the roles that Mll plays in neural lineage specification, we will pursue three specific aims utilizing our conditional knockout mouse model.
In Aim 1, we will further identify and characterize the Mll-dependent lineages from the SVZ, the largest repository of NSCs in the adult mammalian brain.
In Aim 2, we will investigate the role that Mll plays in the NSCs of the dentate gyrus subgranular layer (SGL), the other postnatal/adult NSC population.
In Aim 3, we will discover the roles that Mll plays in embryonic neural development by targeting Mll deletion to a broader and earlier population of NSCs. Together, data from these Aims lay the groundwork for current and future investigations of how distinct neural lineages are epigenetically "programmed" by specific chromatin remodeling factors.

Public Health Relevance

Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms by which NSCs differentiate into neurons and glia is key to unlocking their therapeutic potential. Our research projects are aimed at determining the molecular mechanisms that regulate neural stem cell (NSC) self-renewal and differentiation. For NSCs to make neurons, daughter cells need to express certain sets of genes while repressing others. The maintenance of such lineage-specific transcriptional programs is in part regulated by chromatin structure - the "packaged" state of DNA with histone proteins. Current work in my lab demonstrates that the MLL chromatin remodeling factor is required for neuronal differentiation from NSCs;glial differentiation occurs normally without MLL, suggesting that MLL maintains a transcriptional program specific for neurogenesis. We have begun to identify the genetic targets of MLL. We plan to use both cell biology and molecular approaches to investigate how MLL maintains a transcriptional program specific for neurogenesis. Such information will contribute prominently to the efforts to "program" specific neuronal lineages from NSCs intended for therapeutic purposes, such as those derived from embryonic stem cells. Thus data from these proposed studies lay the groundwork for the development of cell-based therapies for both service-related injuries as well as neurodegenerative diseases in our veteran population.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000252-03
Application #
8195891
Study Section
Neurobiology E (NURE)
Project Start
2009-04-01
Project End
2012-09-30
Budget Start
2011-10-01
Budget End
2012-09-30
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Veterans Affairs Medical Center San Francisco
Department
Type
DUNS #
078763885
City
San Francisco
State
CA
Country
United States
Zip Code
94121