The acquisition of shape by tissues and organs during embryogenesis requires coordinated cell rearrangements. An elegant example of how the reorganization of cells help to shape the embryo is the process of convergent extension. This process was first described in 1895, when investigators observed that pins sparsely inserted in fish embryos converged towards a central location as the embryo developed, and that these movements correlated with the transformation of the embryo from a rounded ball of cells to an elongated (or extended) structure with anterior-posterior polarity. Since then, more sophisticated techniques have revealed that convergent extension promotes elongation of embryonic structures in a variety of model organisms and developmental contexts.
Convergent extension has been widely studied in frogs, fish and flies, but the cellular and molecular mechanisms that control this process in mammals are less well understood. This project focuses on the study of ZFP568, a Krüppel-Associated-Box (KRAB) Zinc finger transcription factor required for convergent extension in mouse. This project uses genetic and molecular approaches to identify the transcriptional targets and effectors of ZFP568. Because KRAB domain proteins are transcriptional regulators exclusively present in the genomes of higher vertebrates, results will shed light on the molecular events that regulate convergent extension specifically in these organisms.
Conditions that affect convergent extension cause severe embryonic malformations. Therefore, by increasing our understanding of the mechanisms that control early mammalian morphogenesis, this study will have a broad impact on the developmental biology scientific community. Scientific education and training will be provided to graduate and undergraduate students as an integral part of the project. The PI and lab also participate in educational outreach activities that promote public awareness of Developmental Biology.
During embryonic development, the acquisition of shape by embryos, tissues and organs requires reorganization of cell populations. Processes such as cell migration, adhesion, proliferation and death are tightly regulated so that individual cell behaviors translate into coordinated rearrangements. One elegant example of highly coordinated cell movements is the process of convergent extension, which mediates the elongation of the embryo along its anterior posterior axis. Convergent extension has been widely studied in frog and fish embryos. However, the factors that control this process in mammals are not very well understood. This project focused on the analysis of two mutations, named chato and chatwo, that disrupt convergent extension in mouse embryos. Intellectual merit. The chato and chatwo mutations were found to disrupt ZFP568 and TRIM28, two transcription factors that form a transcriptional repressive complex. By studying the genes disrupted by these mutations, this project provided information about the molecular mechanisms involved in the control of convergent extension in mammals. Additionally, by analyzing the abnormalities caused by the chato and chatwo mutations in embryos, we uncovered novel functions of ZFP568 and TRIM28 in other processes, including the formation of an intestinal tube from the primordial gut epithelia, and the regulation of genomic imprinting, a process that regulates the expression of genes depending on their maternal or paternal inheritance. Broader impacts. The project provided important contributions to the current understanding of the genes and processes that control early mouse development. The project produced results for several peer-reviewed publications, as well as numerous contributions at scientific conferences. Three graduate students and four undergraduates were trained in molecular biology, genetics and developmental research. The project also supported several outreach activities, including a mouse enrichment extracurricular activity for Cornell undergraduate students and a program on embryonic development that is now offered annually through the Cornell 4H career exploration program.
