This is the first installment in a new series of blog posts from PLOS Genetics about our monthly issue images. Ian Smyth and Tia DiTommaso talk about October’s image from their article, DiTommaso et al.
Authors: Ian Smyth and Tia DiTommaso (Monash University, Australia)
Competing interests: Ian Smyth and Tia DiTommaso are authors of the two papers discussed in this blog.
The skin is the body’s largest organ and it is exquisitely adapted to support life in the harsh, gaseous, terrestrial environment in which we live. One of its principal roles is to maintain “barrier function” – in essence preventing “bad” things from entering your body (bacteria, chemicals etc.) and ensuring the good things (like water) are retained. It also has important functions in repair (wound healing), thermoregulation and in providing a front line in immune surveillance. A particular feature of skin is its regional specialization to form structures like hair follicles and secretory sebaceous glands, both of which are featured on this month’s cover. In this issue of PLOS Genetics, we describe the application of a “reverse genetics” screening approach to identify new genes which play important roles in maintaining the normal function of the skin.
Since the skin comprises most of the surface of the body it is supremely accessible, making it an attractive organ in which to assess gene function in experimental models. Doing so in the mouse is particularly relevant for understanding human disease, because of the genetic and physiological similarity between the two organisms. We took a high throughput approach to assessing gene function in the skin; systematically inactivating genes in mice and then asking what effect this had on skin development and structure. In total examining the potential contributions of more than 500 genes to skin biology, identifying many novel factors that were important for different skin functions .
One such gene, Keratin76 (Krt76), seemed to play a particularly important role in skin biology. The keratins encode a large family of proteins which form networks in the cells of epithelial organs (like the skin) and which contribute greatly to their structural integrity. It was found that Keratin76 was required both for the normal process of wound healing and to maintain the waterproofing “barrier” function of the skin. Interestingly, neither of these features seemed to be associated with a role for Keratin76 in maintaining structural stability, because cell lysis or tissue blistering was not evident in mice lacking the gene. Instead, defects were described in the function of structures called “tight junctions”; microscopic connections which form a seal between neighboring skin cells. To understand this finding better, they examined whether the proteins which normally assemble to form the tight junction were present in cells lacking Keratin76. Strikingly, one of the principal protein components of the tight junction, Claudin 1, was mislocalised. The normal localization of Claudin1 is shown in the featured image, where it is found on the surface of skin cells in the normal hair follicle. Images of this type were key to highlighting a possible link between Keratin76 and Claudin1 and they provided the starting point for molecular studies confirming that the two proteins were physically as well as functionally associated. Our paper therefore proposes that Keratin76 contributes to normal tight junction function by ensuring that Claudin1 localises appropriately to the structure .
These studies are important for a number of reasons. Firstly, they highlight the potential for large scale “reverse genetic screens” in mice to identify new genes important for the biology of different organs. Secondly, they provide one of the first descriptions of an association between keratins and tight junctions themselves. Finally, they challenge the historical view that keratins are simply structural scaffolds, in so doing adding to an emerging body of research which indicates a much more active role in the biology of the cell. Although considerable work remains to elucidate the mode of action of Keratin76 (and indeed the many other genes identified in the screen), this work establishes important precedents for our understanding of the biology of your largest organ.
1. DiTommaso T, et al. (2014) Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse. PLoS Genetics 10(10):e1004705. doi:10.1371/journal.pgen.1004705