How do astrocytes shape brain development?
Astrocytes, a major glial cell type in the brain, are morphologically complex cells that extensively infiltrate the neuropil to directly interact with neurons and all other brain cell types. Through this network of interactions, astrocytes control a wide variety of processes that are fundamentally important for proper brain development and function, including synapse formation, regulation of neurotransmission, and establishment of the blood-brain barrier.
Despite the many vital functions of astrocytes, the cellular and molecular mechanisms that drive the development of astrocyte morphological complexity and regulate astrocyte interactions with other cells are poorly understood. Furthermore, astrocyte dysfunction is implicated in many neurological disorders, however, whether disruptions to astrocyte development and function drive disease pathogenesis is unknown. To address these critical knowledge gaps, our laboratory studies fundamental aspects of astrocyte cell biology, to reveal how astrocytes, through their interactions with other brain cell types, regulate proper brain development and function. Furthermore, we investigate how astrocyte dysfunction drives the pathogenesis of neurodevelopmental disorders.
Molecular mechanisms of astrocyte cell adhesion
A single astrocyte in the mouse brain extends numerous fine processes to contact more than 100,000 individual synapses. In the human brain, this number is greater than 2,000,000! In addition to contacting synapses, astrocytes interact with nearly every other cell type and structure in the brain, including other astrocytes, oligodendrocytes, neuronal cell bodies, and the vasculature. Astrocytes express cell-adhesion molecules throughout their membranes that may participate in these interactions with other cells. How do astrocytes leverage their cell adhesion molecules to establish specialized contacts with different cell types during brain development? We are using primary cell culture, mouse genetics, proximity-based proteomic strategies, and super resolution microscopy to answer this question.
Astrocytes form distinct, non-overlapping territories to tile the brain. This evolutionarily conserved phenomenon is observed from fruit flies to mammals. How do astrocytes establish and maintain their territories? Is tiling important for proper brain function? In a recent study, we found that the cell adhesion molecule hepaCAM regulates astrocyte competition for territory during brain development. When hepaCAM is lost from one astrocyte, the neighboring astrocytes invade its territory. Deleting hepaCAM from all astrocytes impairs astrocyte gap junction coupling and alters synaptic excitation and inhibition. Mutations in human hepaCAM are known to cause brain disorders in human, including megalencephalic leukoencephalopathy with subcortical cysts (MLC), a progressive disorder that affects brain development and function. Current projects in the lab are investigating how human disease mutations impact the function of hepaCAM during brain development, and the impacts of these mutations on astrocyte and synapse development and function. Read more about our findings here.
More details on research projects coming soon. Check back for updates!