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H. Joseph Yost

Professor of Oncological Sciences

B.S. Creighton University

Ph.D. University of Chicago

Research

References

joseph.yost@hci.utah.edu

Joe Yost's Lab Page

Research

Research Overview.   All animals start life as a single cell, the fertilized egg, which divides into hundreds of different cell types. Our long-term research goal is to understand the genes, molecules and developmental mechanisms that regulate the assignment of different cell identities in functionally appropriate positions in the developing vertebrate embryo. This interest takes us in a variety of directions. Understanding these pathways will give us a greater understanding of normal development, aberrant development and cancer development.

Left-Right Axis Formation.   Joseph Yost is a founder and leader in the field of vertebrate left-right development.   His research, currently funded by three NIH grants, utilizes zebrafish, Xenopus and mice to discover the genes, molecular and cellular mechanisms that control asymmetric development of the brain, heart and gut. This research has enhanced our understanding of complex congenital cardiovascular disease, giving insights into complex cardiovascular defects that are among the leading causes of death in the first year. It has uncovered novel mechanisms that regulate cell signaling pathways, cell migration, and embryonic patterning. Given the importance of functional asymmetry in the brain, long-term work on the development of asymmetric gene function in the brain will provide insights into behavioral genetics.

Proteoglycans and Glycobiology of Cell Behavior. Our discovery that syndecans (heparan sulfate proteoglycans) control complex cell signaling pathways, cell migration and fibrillogenesis during development led us to focus on the genetics of proteoglycan function. The combinatorial complexity of fine structure modifications of carbohydrate chains on the surface of cells provides enormous molecular diversity, dwarfing the informational content of the genome. It is becoming clear that a variety of developmental processes, including cell signaling, cell migration, cell-matrix interactions and metastasis, are controlled by the proteoglycan information on the cell surface.

Figuring out how this molecular diversity is regulated and how it is utilized in biology will be one of the major challenges in the "postgenomic era"   and will provide important therapeutic targets for a wide range of human diseases. We have identified large families of genes in zebrafish and Xenopus that control the biochemicals steps that generate complex diversity at the cell surface. We are using the power of zebrafish genetics and embryology, combined with carbohydrate structural biology, to dissect the decisions within a cell that control the carbohydrate information at the cell surface, and the cellular processes (including cell-cell signaling, migration, and metastatic behavior) that are controlled by carbohydrate fine structure.

Cancer Genetics. Our interest in cardiovascular development gave us a unique developmental genetics perspective to approach the question of what goes awry in blood development causing childhood leukemia. What is striking about childhood cancers is that two children can have the same primary mutation, e.g. a specific translocation, and yet one does well with current cancer treatments and the other does not survive. To a geneticist, this implicates modifier genes in other places in the genome that decide between survival and death in the context of the primary mutation. In childhood cancers, traditional human genetics approaches will not work to identify modifier genes, yet modifier genes, unlike the altered transcription factors from the primary mutation, are the best candidates for molecular therapeutics.   Therefore, we have turned to transgenics in zebrafish to model specific leukemias, and are using these models in genome-wide mutants screens to identify modifier genes. In addition, we are using zebrafish genetics to identify novel genes in cancer-related apoptotic pathways. Our long-term goal for this program is pharmacogenetics; to assess the interactions of specific genomes, carrying multiple modifications, with pharmacological candidates.

Zebrafish Genomics. Recent morpholino technology allows us to eliminate the expression of specific genes in zebrafish or Xenopus during early development. We have developed novel technologies to knockdown gene function in specific cell lineages. However, we want the next steps that will allow temporal and spatial control of gene function throughout the life of the organism. We are taking several parallel approaches to develop targeted gene knock-in and knock-out technologies in zebrafish that will confer exquisite control of gene function. This will allow us to more fully manipulate the zebrafish genome, making zebrafish a premier model system to understand human genetic disorders, including specific cancers and complex heart disease.

References