Affiliations: 1) University of Iowa. Department of Biochemistry and Molecular Biology; 2) University of Iowa. Stead Family Department of Pediatrics
Keywords: b. oogenesis; b. germline stem cell
The nuclear envelope is a complex structure that defines the cellular nucleus. Lying beneath the inner nuclear envelope is the nuclear lamina (NL), a protein network comprised of lamins and lamin-associated proteins. One abundant protein in this network is the Barrier-to-Autointegration Factor (BAF), a small dimeric protein that binds the NL LEM domain proteins, histones, and DNA, all properties that contribute to the organization of chromatin within the nucleus. Mutations in the amino terminus of BAF cause human diseases associated with age-related declines in tissue function, including Nestor Guillermo progeria (NGP) and neuromuscular disease (NMD). To gain insights into the mechanism of these diseases, we are modeling disease associated mutations in Drosophila BAF, a protein with 63% identity to human BAF. We are investigating the effects of the disease variants of BAF on the ovary, as BAF is essential for sustained oogenesis. We find that oogenesis is impaired in NGPs flies, with females laying few eggs that do hatch. Our data suggest that reduced egg production is linked to altered GSC mitosis, leading to increased DNA damage and death of transit amplifying cells, defects associated with activation of the DNA damage response kinase Checkpoint kinase 2. We are initiating studies of the NMD variant. Our Drosophila studies of the NMD variant will build from our observations that NMD patient fibroblasts display age-dependent increases in nuclear ruffling, higher levels of heterochromatin, and increased DNA damage, defects linked to changes in the cell cycle that lead to faster proliferation. Taken together, our studies will provide an understanding of the role of BAF in development and tissue homeostasis.