The ectodysplasin pathway: from diseases to adaptations Alexa Sadier, Laurent Viriot, Sophie Pantalacci, and Vincent Laudet Institut de Ge ´ nomique Fonctionnelle de Lyon, Universite ´ de Lyon, Universite ´ Lyon 1, Centre National de la Recherche Scientifique (CNRS), Ecole Normale Supe ´ rieure de Lyon, 46 alle ´ e d’Italie, 69364 Lyon CEDEX 07, France The ectodysplasin (EDA) pathway, which is active during the development of ectodermal organs, including teeth, hairs, feathers, and mammary glands, and which is crucial for fine-tuning the developmental network con- trolling the number, size, and density of these struc- tures, was discovered by studying human patients affected by anhidrotic/hypohidrotic ectodermal dyspla- sia. It comprises three main gene products: EDA, a ligand that belongs to the tumor necrosis factor (TNF)-a family, EDAR, a receptor related to the TNFa receptors, and EDARADD, a specific adaptor. This core pathway relies on downstream NF-kB pathway activation to regulate target genes. The pathway has recently been found to be associated with specific adaptations in natural popula- tions: the magnitude of armor plates in sticklebacks and the hair structure in Asian human populations. Thus, despite its role in human disease, the EDA pathway is a ‘hopeful pathway’ that could allow adaptive changes in ectodermal appendages which, as specialized interfaces with the environment, are considered hot-spots of mor- phological evolution. Ectodermal dysplasias In a section of his 1875 book The Variation of Animals and Plants under Domestication, Charles Darwin discusses that ‘skin and the appendages of hair, feathers, hoofs, horns and teeth, are homologous over the whole body’. In this very same section entitled ‘Correlated variation of homologous parts’ he describes the case of a ‘Hindoo family in Scinde, in which ten men, in the course of four generations, were furnished, in both jaws taken together, with only four small and weak incisor teeth and with eight posterior molars. The men thus affected have very little hair on the body, and become bald early in life. They also suffer much during hot weather from excessive dryness of the skin. It is remarkable that no instance has occurred of a daughter being thus affected’ [1]. In a few sentences he described what became known as anhidrotic/hypohidrotic ectodermal dysplasia (HED) and rightly pointed out two striking features of this disease: it affects several ectodermal organs in a correlated manner, and predominantly affects men (one of the genes responsible is carried by the X chromosome). HED is in fact one of many (more than 150) relatively rare diseases, collec- tively termed ectodermal dysplasias, that affect the skin and other ectodermal organs. In HED (OMIM 257980), patients lack hair (hypotri- chosis), teeth (oligodontia), and nails. Teeth are often malformed in these HED patients. Sweat gland deficiency (anhydrosis/hypohydrosis) explains the inability to resist high temperatures mentioned by Darwin. Several other glands are also affected, including the lacrimal glands, the sebaceous glands, the Meibomian glands, and possibly mucous glands in the respiratory tract. Many affected individuals present a characteristic facial appearance (prominent forehead, thick lips) and in some cases an immune deficiency has been observed [2,3]. It is fascinating that this example, reported by Darwin as an interesting case of pathological variation in human, is now a seminal example of how signaling pathways can affect human health as well as be recruited in wild species for specific adaptations. Two cases have been particularly illustrative in that respect: in stickleback a variant of eda is associated with variation in the defensive armor [4], and in human a point mutation in the receptor EDAR has been shown to be under positively selection and has been linked to hair thickness and specific tooth morphology [5]. Here we re- view these two cases and discuss the implications of this dual link between human disease and natural variation. From human genetics to animal mutants More than 120 years after Darwin made his observations, the gene mutated in the X-linked forms of the disease was first mapped on chromosome X of male patients and later identified using rare female patients that harbor an X:au- tosome translocation [6,7]. This gene was termed EDA for ectodysplasin in reference to the disease. A very similar phenotype (hair defects, tooth abnormalities, and absence of sweat glands [8]), had been described in the mouse spontaneous X-linked mutant tabby. This facilitated the cloning of the Eda/tabby gene, the mouse ortholog of the human EDA gene [9,10], and eventually pointed to the fact the encoded protein was a member of the TNF superfamily. From then on mouse mutants which closely resemble the tabby mutant enabled the identification of other genes of the core ‘EDA pathway’. The mouse mutant downless led to the Edar gene, a member of TNF receptor superfamily ([11,12], reviewed in [13]). Lastly, the crinkled mouse Review 0168-9525/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tig.2013.08.006 Corresponding author: Laudet, V. (Vincent.Laudet@ens-lyon.fr). Keywords: ectodysplasin; anhidrotic/hypohidrotic ectodermal dysplasia; adaptation; ectodermal appendages; signaling pathways. 24 Trends in Genetics, January 2014, Vol. 30, No. 1