ROBERT VRIES · Functional Understanding of Neuron Specific ATP-Dependent Chromatin Remodeling Complexes
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-07-01 → 2007-06-30
- EU contribution
- €260,624
- Participants
- 1
- Scheme
- OIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - ROBERT VRIES (Functional Understanding of Neuron Specific ATP-Dependent Chromatin Remodeling Complexes)
During development from a stem cell to a fully differentiated cell, a cell undergoes dramatic changes. Gene expression, responsible for the transitions, is very tightly regulated during all stages of development. An important mechanism used to regulate gene expression is by changing the structure of the chromatin switching between an active and an inactive chromatin stage. Once a set of genes is activated or inactivated, this stage can be maintained during generations of cells. One important group of proteins involved in this epigenetic regulation of gene expression is the BAF family of proteins. The BAF complexes contain about 10 subunits including an ATPase, such as BRG1, together responsible for remodelling the chromatin. We are studying the role of the Brg1complex in the differentiation of a neural stem cell to a neuron. Our studies showed that: 1) The complex has specific subunits for every stage of development. A switch between the different subtypes of the BAF complex is necessary for the cell to differentiate to a neuron and vice versa for maintaining a stem cell. Misexpression of any of the subunits results in failure of a cell to maintain stem cells or to differentiate. 2) One of the families of transcription factors of the complex is BAF53 of which two subunits exist. Our studies identified that BAF53b is specifically required for dendritic outgrowth. Expression of BAF53a in a BAF53b negative cell fails to restore the phenotype resulting from the BAF53b deletion.
Data: CORDIS, © European Union
Project objective
Mammalian cells contain polymorphic ATP-dependent chromatin remodeling complexes similar to the yeast SWI/SNF complex. Because these complexes contain several subunits (including actin as well as DNA binding subunits) that are not present in the yeast complex the name BAF complexes have been adopted to raise a note of caution concerning mechanistic extrapolations. Recent work in the Crabtree laboratory has indicated that during neural development a series of these BAF chromatin remodeling complexes are expressed as cells differentiate from non-committed stem cells to periventricular neural stem cells to post mitotic neurons. For example, post mitotic neurons express the neural specific BAF53b protein, an Actin Related Protein (ARP) that occupies the place of BAF53a in the ubiquitous BAF complexes. Purification of the post mitotic neural-specific complex indicates that it contains at least 2 other subunits that are present only in neurons. Immunocytochemistry indicates that periventricular neural stem cells do not express BAF53a or b, suggesting that they have a specific complex. My goal will be to precisely define the components of the complexes present at different stages of neural development using the most recent and sensitive proteomic methods. I will be using mouse model system with different neuronal specific deletions of the BAF complex subunits such as Baf 53b and BrgI which have already been made in the Crabtree lab. If I confirm the substantial preliminary data that a neural specific complex is present, I will set out to understand why neural stem cells should have such a complex and weather or not it plays a role in the genomic plasticity associated with the stem cell state.
Original text from CORDIS.
Participants
- KONINKLIJKE NEDERLANDSE AKADEMIEVAN WETENSCHAPPEN · AMSTERDAMCoordinatorNetherlands
Links
Data: CORDIS, © European Union