A guardian of balance: the role of BAF chromatin remodeling complex in astrogliogenesis during mouse forebrain development

by Kamila Anna Kiszka
Doctoral thesis
Date of Examination:2019-05-15
Date of issue:2019-12-20
Advisor:Prof. Dr. Jochen F. Staiger
Referee:Prof. Dr. Jochen F. Staiger
Referee:Prof. Dr. Thomas Dresbach
Persistent Address: http://dx.doi.org/10.53846/goediss-7790

 

 

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Abstract

English

In the human central nervous system, astrocytes vastly outnumber neurons and regulate a host of physiological processes critical to its function. Astrocytes form a functional syncytium tiling the brain with minimal overlap between individual cells. This anatomical organization implies that a balanced numbers of neurons and astrocytes must be generated during brain development. In spite of this, very little is known about the molecular events governing proliferation and differentiation in the astroglial lineage that culminate in the establishment of adequate numbers of astrocytes. In recent years, the chromatin remodeling BAF (Brg1/Brm Associated Factors) complex, a conglomerate of at least 15 protein subunits, has emerged as a key regulator of different steps of neurogenesis, from proliferation of progenitors to differentiation into mature neurons, thus profoundly affecting brain development. However, its functions in astrogliogenesis are largely unknown. Here, we investigated the involvement of BAF complex in the regulation of cellular proliferation and differentiation in the astroglial lineage of perinatal mouse brain. We first assessed the expression of several BAF complex subunits in cells of both neuronal and astroglial lineages, and found that the composition of the BAF complex was cell type dependent. Next, we examined the phenotype of a mouse model in which hGFAP-Cre driven conditional knockout of BAF155 and BAF170, two scaffolding subunits, results in the deletion of the entire BAF complex within radial glial progenitors during late neurogenesis and astrogliogenesis. Performing phenotype and gene expression profile analyzes, we found that loss of BAF complex at this developmental stage causes a tremendous depletion of neuronal cells as well as an aberrantly increased abundance of proliferative astroglia in ventral and dorsal telencephalon. Furthermore, we identified an upregulated expression of GLI1 as a causal mechanism of abnormal overproliferation of astroglial cells following BAF complex depletion. This could be demonstrated by inhibition of GLI1 by injection of GANT61, which abolished the aberrant proliferation caused by loss of BAF complex. We thus propose that cell lineage dependent rearrangements of the composition of the BAF complex play a crucial role in regulating the relative numbers of neurons and astrocytes generated during brain development. This effect is achieved in part by BAF complex dependent repression of the proliferation-enhancing mitogen GLI1 in the astroglial lineage.
Keywords: BAF complex, astrogliogenesis, mouse development
 
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