The development of the vertebrate nervous system requires switching of polymorphic ATP-dependent chromatin remodeling complexes from a neural progenitor complex (npBAF) to a neuron-specific complex (nBAF) at mitotic exit. This switch is in part directed by two microRNAs, miR-124 and miR-9, which when expressed in fibroblasts can convert them into functional neurons. Recent exome sequencing studies have found frequent mutations of BAF complex subunits in non-syndromic mental retardation, microcephally, schizophrenia and less frequent BAF complex mutations in sporadic autism and sporadic ALS. The apparently genetically dominant nature of these mutations is consistent with the instructive role of subunit switching during neurogenesis and suggests that these chromatin regulators may have rate-limiting functions. Relatively little is known of the underlying mechanisms directing subunit switching, or how subunit switching relates to other more well-defined programs of neural development. Also, the mechanisms underlying the contribution of subunit mutations to a diverse range of neurologic diseases in humans are unknown. Indeed most of the mutations are in subunits not required for conventional activities such as nucleosome remodeling. Our preliminary data suggest that repression of three progenitor subunits and their substitution with neuron-specific subunits leads to mitotic exit of neural progenitors (NPGs) and functional differentiation. We will test this hypothesis using genetic approaches and define the genetic circuitry involved in repression of the npBAF subunits and the activation of the nBAF subunits. We will also define the proteins that bind to the neuron- specific surfaces of the complexes that mediate their role in dendritic morphogenesis, dendritic targeting and neural fate determination. Using chromatin immunoprecipitation and sequencing we will define the genome- wide consequences, which result from the normal exchange of three subunits within these 2 mega dalton chromatin remodeling complexes. Our studies and those of others indicate that an important function of BAF complexes is to oppose Polycomb complexes;however the mechanisms underlying this opposition are not understood. Thus, we will use a method recently devised in our lab to understand the underlying mechanism of BAF-Polycomb opposition. At the conclusion of our studies we hope to have an understanding of the fundamental genetic circuitry and mechanisms critical for this epigenetic switch and to gain insight into the roles of polymorphic BAF complexes in diverse human neurologic diseases.

Public Health Relevance

Recent genetic studies have found that individuals with different neurologic diseases frequently have mutations in chromatin regulatory complexes. These complexes control the way that DNA (our genetic material) is packaged into cells and yet made available to regulatory mechanisms. Specific chromatin regulatory complexes are found only in neurons. Directing the formation of these neuron-specific complexes in human skin cells can convert them to functional neurons opening new avenues for disease modeling, drug testing and perhaps replacement of damaged neurons. We will study how these complexes function in normal brain development so that we might understand how they malfunction in mental retardation, schizophrenia, autism and a growing list of neurologic diseases.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS046789-12
Application #
8702240
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Staahl, Brett T; Tang, Jiong; Wu, Wei et al. (2013) Kinetic analysis of npBAF to nBAF switching reveals exchange of SS18 with CREST and integration with neural developmental pathways. J Neurosci 33:10348-61
Ronan, Jehnna L; Wu, Wei; Crabtree, Gerald R (2013) From neural development to cognition: unexpected roles for chromatin. Nat Rev Genet 14:347-59