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What are the functions of all that stuff outside of cells–the extracellular matrix?
The worm cuticle is a complex composite of many different types of proteins, a number of which are also found in human skin, such as collagens. Being outside the cell, this composite is referred to as an extracellular matrix (ECM). Different types of ECMs function in different locations and at different times throughout the lifetime of an organism. Cells secrete the building blocks and enzymes required to assemble and modify the ECM. The ECM in turn affects many aspects of cell behavior, organization, and function. Accordingly, ECM defects lead to a wide array of diseases including birth defects, connective tissue disorders, cardio-pulmonary syndromes, and cancer.
In something of a coincidence, a completely separate line of studies–ones having nothing to do with molting–led us to discover a role for the ECM surrounding the worm embryo. This ECM, termed the sheath, is a precursor to the larval and adult cuticle. We found that the embryonic sheath is required for the developing worm to withstand several intrinsic biomechanical forces that arise during worm morphogenesis–the process whereby an oval blob of cells transforms into a beautiful worm. Notably, defects in the sheath lead to abnormal morphogenesis and embryonic lethality (Figure 1). In fact, some of the same genes that we found to be important during embryogenesis are also important for molting during larval stages. One example is FBN-1, which encodes a protein similar to human fibrillins that are mutated in Marfan Syndrome. Moreover, several of the genes we discovered appear to function in intracellular trafficking, further merging our two seemingly independent lines of research (Figure 1).
Developing genetic and computational toolsforstudies in worms.
As part of our research program, we are working to develop tools and procedures that may be of use to the greater scientific community. Some of these have involved genetic strategies and bioinformatic pipelines to help expedite the identification of the relevant mutated genes inspecific mutant worms. When scientists carry out genetic screens to obtain mutants, such as those causing defects in molting or embryogenesis, they are generally most interested in determining which one of the 20,000 possible genes contained the mutation that caused the observed defect. This is a bit of a needle in a haystack problem and can be compounded by a number of complicating factors. One of our innovations was to develop a strategy termed the Sibling Subtraction method, which can help to streamline this process (Figure 2).
More recently, we developed a computational tool to help scientists with their CRISPR experiments. CRISPR is a tool used to make edits to the genomes of cells and animals, and its discovery and development led to the 2020 Nobel prize in chemistry. Our tool, called CRISPR cruncher, aids scientists in the design of CRISPR experiments so that they can identify useful genomic edits more efficiently. This tool was developed in collaboration with the Wyoming INBRE Bioinformatics Core, which was also instrumental in our development of the Sibling Subtraction method.