Mechanism of an epigenetic switch that mediates neural development
Abstract/Contents
- Abstract
- During the development of the vertebrate nervous system neural progenitors divide, generate progeny that exit mitosis and then migrate to sites where they elaborate specific morphologies and synaptic connections. Mitotic exit in neurons is accompanied by an essential switch in the Mammalian SWI/SNF (also called BAF) ATP-dependent chromatin regulatory complexes from the neural progenitor npBAF to neuron-specific nBAF complexes. We elucidated the mechanism of a microRNA/chromatin switch underlying the switch of the npBAF subunit, BAF53a for the nBAF subunit BAF53b. Recapitulating this microRNA/chromatin switch in fibroblasts leads to their direct conversion to neurons. We have defined the kinetics of nBAF complex assembly in the formation of induced neurons from ES cells or fibroblasts as well as normal neural differentiation and using proteomic analysis find that this switch also includes the removal of SS18 and its replacement by CREST at mitotic exit. We find that switching of chromatin remodeling mechanisms is highly correlated with a broad switch in the use of neurogenic transcription factors. Knockdown of SS18 in neural stem cells causes cell-cycle exit and failure to self-renew, while continued expression of SS18 in neurons blocks dendritic outgrowth underlining the importance of subunit switching. Recent whole genome sequencing studies show that dominant mutations in BAF subunits underlie widely different human neurologic diseases including mental retardation, microcephally, schizophrenia, sporadic mutations in autism as well as the neurodegenerative disease, amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's disease. Using whole exome analysis of ALS trios (trio=two unaffected parents and affected child), we identified and functionally characterized two de novo mutations in CREST that function in a dominant negative mode to inhibit dendrite outgrowth in cortical and motor neurons. As the aforementioned neurological diseases arise in different neuronal types, our studies suggest that the characteristics of these diseases must be interpreted in the context of the different BAF assemblies in neurons rather than a singular mSWI/SNF complex.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2013 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Staahl, Brett Theodore |
|---|---|
| Associated with | Stanford University, Department of Developmental Biology. |
| Primary advisor | Crabtree, Gerald R |
| Thesis advisor | Crabtree, Gerald R |
| Thesis advisor | McConnell, Susan K |
| Thesis advisor | Nusse, Roel, 1950- |
| Thesis advisor | Scott, Matthew P |
| Advisor | McConnell, Susan K |
| Advisor | Nusse, Roel, 1950- |
| Advisor | Scott, Matthew P |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Brett Theodore Staahl. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Ph.D. Stanford University 2013 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2013 by Brett Theodore Staahl
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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