Receptor-interacting serine/threonine-protein kinase 4 (ripk4) induces epidermal differentiation in early zebrafish embryos independently of inhibitor of nuclear factor kappa-B kinase subunit 1 (ikk1)
Grzegorski, Steven J.
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The epithelium is the outer most layer of cells responsible for mediating the interactions of an organism with its external environment. Squamous cells are scale-like flattened cells that form the most superficial layer of the epithelium. Regulatory errors in these cells can lead to squamous cell carcinoma, the second most common form of skin cancer. Understanding of the underlying molecular mechanisms is integral for improved diagnostics and therapeutics. IKK1 is a known regulator of several important pathways including regulation of epidermal differentiation and proliferation. Changes in IKK1 expression have been linked to tumor proliferation in squamous cell carcinomas. IKK1 -/- knockout mice have proven critical in understanding the function of IKK1 but are difficult in studies of early epidermal development. The novel zebrafish maternal-effect mutant poky contains a mutation in the zebrafish homolog ikk1. This study focuses on a related protein kinase called Ripk4. The mouse homolog RIP4 is a known upstream activator of IKK1 in some pathways. Additionally, RIP4 -/- knock out mice display a hyperproliferative epidermis that fails to terminally differentiate. This phenotype is similar to what is observed in IKK1 -/- KO mice. For this study, several mutant forms of the ripk4 construct were made to investigate its role and relationship to ikk1 in early epidermal development. Three forms were made in an effort to knock out function in addition to a fourth constitutively active form. The study revealed that ripk4 is sufficient but not necessary to induce markers of epidermal differentiation in early embryos. Furthermore, it was revealed that the constitutively active Ripk4 was able to induce differentiation in poky mutants. This clarifies the relationship between ripk4 and ikk1, and supports the idea that ripk4 acts parallel or downstream of ikk1 in some pathways.
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