Corey Harwell, PhD, assistant professor of neurobiology
The Zika virus is a mosquito-borne virus that was first identified in Africa in 1947 and has recently spread in the Americas, leading the World Health Organization to declare the virus an international public health emergency in 2016. Zika infects cells of the central nervous system and causes microcephaly—a condition in which infants are born with a smaller brain and head. The characteristic feature of microcephaly is a dramatically reduced cerebral cortex, the grooved surface of the brain that regulates many aspects of cognitive function, such as language development, reasoning, and motor planning.
My laboratory studies the cellular and molecular mechanisms that regulate the production and diversity of cells in the cerebral cortex. The cerebral cortex is home to heterogeneous populations of neurons that vary in their morphology, function, and molecular profile. Intriguingly, the heterogeneous population of neurons in the adult brain arises from a pool of neural progenitor cells (NPC) found in the developing cerebral cortex. NPCs are the fundamental pieces that build the cortex, the precursors to mature neurons through regulated and repeated cell division. Through complex genetic programs, these neural progenitors eventually give rise to the diversity of cell types that comprise the mature cerebral cortex.
We know that Zika causes microcephaly because studies have demonstrated that the virus causes death of NPCs and disrupts their ability to proliferate via cell division, leading to a reduced cortex. This indicates that the number of NPCs produced by cell division is a key part of healthy cortical development. Thus, we are deeply interested in understanding the basic mechanisms of how neural progenitors decide when and how often to divide and, eventually, what subtype of cortical neuron they will mature into.
Specifically, my laboratory is examining a class of proteins known as chromatin-modifying enzymes, which bind to and alter the 3D structure of DNA. These changes in structure can profoundly affect whether a gene encoded by the DNA is active and functional in the cell, which ultimately influences what kind of neuron that NPC will become in the adult cortex. Notably, many of the genes associated with neurodevelopmental disorders code for these chromatin-modifying enzymes, further indicating their importance in healthy brain development.
We have found that the modification of chromatin structure by these enzymes during development of the cerebral cortex is of fundamental importance. However, we do not know exactly when during development or which genes are affected by these modifications. Ultimately, our goal is to understand the developmental patterns of chromatin modifications in NPCs so as to understand how diverse cell types in the cortex assemble into functional neural circuits.