Continuing studies about an important regulatory protein kinase complex called I-kappa-B kinase (or IKK) have now shown that a subunit of IKK – IKK alpha – influences the outer layer of skin in developing mice to control the eventual shape of the full-grown skeleton and skull.
University of California, San Diego (UCSD) School of Medicine researcher Michael Karin, Ph.D., first discovered the IKK complex and its three sub-units, alpha, beta and gamma in 1996. Since then, his group has published extensively on the numerous activities of IKK sub-units, including roles in immune response activation, in formation of the skin’s outer layer, and as an essential protein that prevents a rare disease called Incontinentia Pigmenti.*
Published in the April 8, 2004 issue of the journal Nature**, the new study illustrates how IKK alpha, acting within the ectoderm, or outer layer of developing skin, relays developmental information to the mesoderm, the middle layer of the developing embryo, which gives rise to the skull, skeleton and musculature.
Scientists already know that mesoderm cells, within the first few hours of development, migrate to the location of skeleton and head where they form a mesh into which bone can be laid. However, this is the first study to graphically illustrate the role of the ectoderm in this process.
The researchers found that one mechanism by which IKK alpha exerts a strong effect on development of cranial and skeletal bone is through regulation of a family of growth factors called fibroblast growth factors (FGF).
“By understanding the processes that control development, we have a new path to pursue for potential treatment of mutations affecting skeletal and craniofacial development in humans,” said Karin, who is a UCSD professor of pharmacology and an American Cancer Society Research Professor.
“It may also turn out that controlling FGF over-expression by IKK alpha could be relevant for certain types of skin cancer,” Karin added. “Although cancer usually appears as we grow older, some of the aberrations that lead to cancer development may have occurred early in life during embryogenesis. In this case, overproduction of FGFs, proteins that stimulate the proliferation of skin cells, may make an important contribution to the eventual development of certain types of skin cancer.”
For their experiments, the investigators utilized IKK alpha-deficient mice who are born with abnormalities that included taut and shiny skin, rudimentary limbs, absent or severely truncated tail, and a short and rounded head due to shorter jaw and nasal bones.
When embryos of IKK alpha-deficient mice were given a version of IKK alpha that deposits itself exclusively in the outer layer of the skin, the newborn mice were normal, with wrinkled and loose skin, well-developed limbs and tails, and a fully normal head.