Molecular Mechanisms of Astrocyte Growth Control.

点击翻译按钮获取中文摘要

Astrocytes are essential to brain function, shaping neurons and their connections and supporting their activity. Astrocytes acquire a remarkably complex morphology to associate with each other, and synapses where they regulate synaptogenesis, neurotransmitter reuptake, metabolic support, ion balance, and ultimately animal behavior. While it is believed that this morphology is absolutely essential for efficient astrocyte function, how astrocytes acquire this unusually complex architecture remains a mystery. This is surprising in light of the fact that disruption of astrocyte growth control results in the most intractable and deadly human brain tumor, glioblastoma. How do astrocytes acquire their remarkably morphology, and how do they organize their subcellular architecture to enable their diverse functions? I will attempt to answer these central questions using Drosophila astrocytes as a model. Fly astrocytes are remarkably similar to their mammalian counterparts by morphological, developmental, molecular, and functional criteria. I will begin by comprehensively characterizing the cell-wide organellar landscape of astrocytes by examining the distribution of ~30 genetically encodable markers that label cellular organelles (Aim 1). This will allow me to define the basic organellar architecture of astrocytes, which is an essential first step toward understanding how their intricate morphology is arranged ultrastructurally and how it dictates function. These cellular landmarks will also enable a rigorous analysis of mutants that affect astrocyte morphology. In Aim 2, I will perform the first unbiased forward genetic screen for astrocyte growth control pathways. We have established a unique genetic screening platform for this purpose in Drosophila based on MARCM technology, which allows for screening of the entire genome for a variety of phenotypes including increased growth, changes in proliferation, or other changes in astrocyte morphology. Defining how astrocytes control their cell growth, infiltration, and tiling is critical to understanding how astrocytes affect brain health and disease. Since this will be the first forward genetic screen for astrocyte growth control pathways, a wealth of exciting mutants await discovery. Novel conserved cellular pathways will be my focus, such that discoveries in the fly can be next translated in vertebrates.