The overall fitness of complex multicellular organisms depends on the successful coordination of multiple tissues. In the course of an organism's life, mitotic events and environmental insults lead to somatic mutations that can produce pools of suboptimal cells that can compromise tissue integrity. In humans, the presence of genetically distinct populations of somatic cells occurs in a number of Mendelian disorders, disorders of chromosomal anomalies like trisomy 21, and cancer. Quality control mechanisms must exist to ensure proper tissue growth and maintenance. Declining efficiency of these mechanisms may explain the increased frequency of tissue mosaicism with age in the human population and the associated disease burden. In flies, a process known as cell competition optimizes tissue health by actively eliminating suboptimal cells. Recent studies have demonstrated that the phenomenon occurs between mouse embryonic stem cells and in the developing mouse embryo, yet the molecular mediators of mammalian cell competition remain unknown. Clarifying the molecular components of this process in mammals would begin to help us grasp its relevance to human health and disease. To that end, this project sets out to characterize a form of postnatal cell competition in the developing mouse retinal and brain vasculature with the hope of developing a basic understanding of the rules governing tissue growth and maintenance. Preliminary data suggests that central nervous system (CNS) endothelial cells (ECs) lacking the transcription factor Zic3 are less fit than ECs that retain a functional copy. Developing CNS vasculature composed of suboptimal Zic3 null ECs and wild-type (WT) ECs might actively detect and eliminate the mutant population. This mechanism may depend on the cells sensing, reporting on, and comparing some intrinsic fitness parameter like proliferative capacity. The ultimate goal of this study is to identify the genes that enable this process in mammalian cells. The proposed research strategy will accomplish this through three specific aims: 1) Test the hypothesis that in developing mosaic CNS vasculature, ECs lacking Zic3 are eliminated in a fashion consistent with cell competition, 2) Establish an in vitro EC competition model and test the hypothesis that ECs interact through secreted signals or direct cell contact in order to establish loser and winner populations, and 3) Determine molecular components of the mammalian cell competition machinery through transcription profiling of loser and winner cells. A combination of histological analysis, cell culture, and next-generation RNA sequencing will be used to address these aims. Understanding how tissue robustness is achieved is paramount to human health as the knowledge could bring us closer to clinical applications of tissue regeneration, help mitigate developmental errors, curtail the impending rise in age-related disease, and extend lifespan.
The disease burden associated with advanced age may reflect the accumulation of somatic mutations in organs and the subsequent presence of genetically distinct populations of cells due to a declining efficiency of mechanisms that optimize tissue health by eliminating suboptimal cells. In addition, tissue mosaicism also occurs in a number of single-gene diseases, disorders of chromosomal anomalies like Down syndrome, and cancer and could explain the population variability in disease risk. This study seeks to characterize one of these quality control mechanisms in the postnatal mouse with the hope of furthering knowledge on natural mechanisms that mitigate developmental errors and achieve tissue robustness.
|Sabbagh, Mark F; Heng, Jacob S; Luo, Chongyuan et al. (2018) Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. Elife 7:|