Vertebrates have internal asymmetries along the left-right axis, including asymmetric placement of the organs. Correct placement of organs, such as the heart, is critical for proper embryonic development and survival. Due to improper gene expression as many as one in 5,000 children are born with left-right patterning defects which often manifest as congenital heart disease. Understanding the genetic pathways involved in establishing proper left-right patterning in the embryo is vital to understanding how these defects may arise. A novel zebrafish mutant, Kurly, affects left-right patterning and subsequent heart development. Interestingly, the novel human ortholog of Kurly maps to a gene located on human chromosome 21 within the Down Syndrome Critical Region. Genes located in this area are perhaps responsible for the high incidence of congenital heart defects in Down Syndrome patients. While 0.8% of the general population is affected by congenital heart defects, 40-50% of those affected by Down Syndrome have congenital heart defects. By understanding how Kurly functions in zebrafish, valuable insight will be gained into how left-right patterning defects and subsequent congenital heart defects may arise. The zebrafish is an excellent model organism due to its external development, transparency, and genetic manipulations that can be made. Also, as many genes involved in left-right patterning have conserved roles in humans, experiments performed in zebrafish and knowledge gained from these experiments are clearly applicable to the greater good of society. To investigate Kurly's effects on left- right patterning and heart development, I will take multiple approaches. I will first use immunohistochemistry and fluorescent protein tagging to examine the location and sites of function for Kurly. I will then explore how Kurly affects primary cilia and cell polarity during these early patterning events by injection assays and immunofluorescence. I will finally identify other proteins that interact with Kurly, through tandem affinity purification, during these stages of development in order to gain insight into significant pathways which may require Kurly function. Relevance: This research greatly benefits mankind through an in-depth analysis of a gene that, when misregulated, leads to left-right internal organ patterning defects as well as congenital heart defects.
| Jaffe, Kimberly M; Grimes, Daniel T; Schottenfeld-Roames, Jodi et al. (2016) c21orf59/kurly Controls Both Cilia Motility and Polarization. Cell Rep 14:1841-9 |
