
Thao P. Phan
I have had the great opportunity to pursue my graduate research work in Andrew Holland’s lab. Our lab is fascinated with cell division and the molecular mechanisms that allow this process to happen precisely every time the cell divides.
My research project focuses on cell divisions that occur during early brain development. Specifically, I was curious as to why mutations in proteins functioning at the centrosome — organelles that help form the bipolar spindle during mitosis, frequently lead to a brain developmental condition called microcephaly. Using mouse models carrying these mutations, I was able to show that during the pathogenesis of microcephaly, neural progenitor cells with centrosome defects take longer to complete mitosis, which in turn activate a signaling axis consisting of 53BP1, USP28 and TP53. Activation of this signaling pathway, collectively referred to as the mitotic surveillance pathway, leads to cell death in the developing brain, resulting in a smaller brain size with fewer neurons. Remarkably, removal of any components of the mitotic surveillance pathway is sufficient to restore neural progenitor proliferation and rescue brain size. These findings suggest that activation of the mitotic surveillance pathway is a central mechanism underlying microcephaly pathogenesis in human patients.