SurveyTNF superfamily in skin appendage development
Introduction
Skin appendages such as hairs, mammary glands, feathers, and scales are class-defining features of vertebrates. Although fully formed skin appendages vary considerably in form and function, their early stages of development are notably similar both morphologically and molecularly [1], [2]. This is reflected in human syndromes known as ectodermal dysplasias (EDs), a large group of congenital disorders characterized by lack or dysgenesis of at least two epithelial appendages [3]. In 1996, Kere et al. reported the identification of the gene mutated in the human X-linked hypohidrotic (or anhidrotic) ectodermal dysplasia (HED or EDA, MIM 305100), the most common form of all EDs [4]. Cloning of the corresponding mouse gene defective in the natural mouse mutant Tabby and the causative genes of the autosomal forms of HED (MIM 129490 and 224900) and their mouse counterparts led to the discovery of a novel tumor necrosis factor (TNF) pathway, the ectodysplasin (Eda) pathway [5], [6].
The Eda pathway consists of the ligand Eda, its receptor Edar, and a cytosolic adaptor molecule Edaradd (Edar-associated death domain) [5]. In humans, mutation in any of the three genes causes identical defects including sparse hair, presence of only few teeth that are typically abnormally shaped (conical), absent or reduced sweating, as well as defects in a number of glands. The inability to sweat may lead to life-threatening hyperthermia in affected children causing high mortality if the syndrome goes unrecognized [7]. The vast majority of HED patients carry mutations in Eda—currently around 90 different mutations in the Eda gene have been reported (The Human Gene Mutation Database; http://www.hgmd.cf.ac.uk) while mutations in the coding regions of Edar or Edaradd account for some (but not all) cases of autosomal recessive and dominant forms of HED [8], [9]. The mouse equivalents for HED, Tabby, downless/Sleek, and crinkled defective in Eda, Edar, and Edaradd, respectively, were described already more than 50 years ago and were shown to be phenotypically alike [5]. The defects of these mice show remarkable similarity to HED including, e.g. absence of sweating.
During the last 10 years, the analysis of the Eda/Edar/Edaradd deficient mouse phenotype has largely focused on the tooth and hair follicle defects [5]. A hallmark of an Eda signaling defect is the absence of guard hairs, which are the long, straight hairs protruding above the plane of the coat [10]. Guard hair follicles are the first pelage hair types to develop; organ primordia are first detected at embryonic day 14 (E14; mouse embryogenesis takes about 19 days) in wild type mice but not in Eda deficient mice. However, the initiation of other types of pelage hair follicles appears to occur normally although the resulting hair shafts are all aberrant [11], [12]. As guard hairs constitute only 2–4% of all fur hairs, the number of hairs in Eda null mice has been estimated to be roughly normal [12], [13]. Analysis of tooth development in Eda−/− embryos shows a progressively more hypoplastic enamel organ during advancing tooth morphogenesis resulting in small teeth with few cusps in adults [5].
It has become apparent that the function of Edar pathway is not limited to mammals. Data from many species imply that not only the sequence but also the function of Edar has been conserved in all vertebrates [6], [14], [15]. Edar has recently been implicated as an important regulator of early feather development [15], [16], [17], and a mutation in the Edar gene of the teleost Medaka fish results in a failure of the development of almost all scales [14]. Thus mammalian hair and tooth, chick feather, and fish scale development involve the same TNF pathway.
Section snippets
Overview of skin appendage development
Organogenesis may be divided into three phases – initiation, morphogenesis, and differentiation – that are all regulated by inductive interactions between different types of tissues. Initiation of skin appendage development is guided by conversation between the ectodermal epithelium and the mesenchyme that can originate from the mesoderm (e.g. mammary gland and body hairs) or the neural crest (tooth and cranial hairs). The cross-talk between and within tissues is mediated by a limited number of
Ectodysplasin signal transmission
The Eda gene gives rise to numerous different transcripts through alternative splicing, but currently the biological relevance of only the longest Eda-A1 and Eda-A2 isoforms has been confirmed [5], [6]. Eda-A1 and Eda-A2 are produced as trimeric type II transmembrane proteins that are released from the cell surface by a furin-mediated proteolytic cleavage [5]. The soluble domain of Eda consists of a C-terminal ∼150 amino acid receptor binding domain that is preceded by a collagen-like domain
Expression of the Eda pathway components
Both Eda and Edar are expressed at low levels throughout the simple embryonic ectoderm prior to any visible sign of developing skin appendages (see [5], and references therein). However, as soon as the organ primordia emerge, expression of Edar gets localized to placodes while Eda shows a complementary expression pattern in the flanking epithelium. During advancing tooth morphogenesis, expression domains of Edar and Eda are largely non-overlapping [5], which may explain the importance of the
Role of ectodysplasin in development
The fact that Eda−/− (lacking all isoforms), Edar−/−, and Edaradd−/− mice have practically identical phenotypes has suggested that the Eda-A2 isoform plays a less significant role in development. This conclusion is supported by absence of any gross abnormalities in Xedar null mice [37]. Likewise, transgenic expression of Eda-A2 did not rescue any of the defects of Eda null mice while Eda-A1 corrected most of them [13], [51]. It is, of course, possible that Xedar acts redundantly with another
Troy
The similarity of the ligand-binding domains of Troy (also known as Taj and Tnfrsf19), Xedar and Edar mark them out as a subgroup in the TNFR superfamily [6], [66]. The details of the Troy pathway have long remained elusive. A recent report suggests that Troy is activated by lymphotoxinα (LTα), a TNF family member [67] while previous studies have not revealed specific interactions between Troy and any of the TNFs [24]. As a soluble homotrimer LTα is known to bind to the same receptors as TNF,
Concluding remarks
The past few years have shed considerable light on the mechanisms by which the Eda pathway regulates initiation of skin appendages. As more and more transcriptional targets of Eda are recognized, our understanding of the functions of Eda is likely to increase considerably in the near future. The consequences of pathogenic mutations in Eda are now rather well characterized. With the help of modern genetic and genomic tools, knowledge on the role of this ancient pathway in generating
Acknowledgements
I thank Irma Thesleff for discussions and comments, and Ingrid Fliniaux and Katja Närhi for illustrations.
Marja Mikkola (née Rikkonen) is a project leader in the Developmental Biology Program of the Institute of Biotechnology at the University of Helsinki, Finland. Dr. Mikkola received her PhD in 1994 in Department of Genetics at the University of Helsinki. She did her post-doctoral training first in the Program in Cellular Biotechnology at the Institute of Biotechnology, and in 1997, she joined the laboratory of Professor Irma Thesleff in the Developmental Biology Program of the same institute.
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2019, iScienceCitation Excerpt :This pathway is important in refining the size, spacing, and shape of various vertebrate skin appendages (Sadier et al., 2014), including the density and patterning of bony armor derived from modified scales of several stickleback species (Colosimo et al., 2005; O'Brown et al., 2015), and the number of scales in Medaka (Kondo et al., 2001). The Eda pathway interacts with other important signaling pathways, including Hh, Wnt, FGF, and BMP, throughout skin appendage development of diverse vertebrates (Mikkola, 2008; Häärä et al., 2011, 2012). Therefore, a shift in Eda signaling may likely underlie the morphological evolution of the dermal skeleton in teleost groups, including the pufferfishes.
Marja Mikkola (née Rikkonen) is a project leader in the Developmental Biology Program of the Institute of Biotechnology at the University of Helsinki, Finland. Dr. Mikkola received her PhD in 1994 in Department of Genetics at the University of Helsinki. She did her post-doctoral training first in the Program in Cellular Biotechnology at the Institute of Biotechnology, and in 1997, she joined the laboratory of Professor Irma Thesleff in the Developmental Biology Program of the same institute. She is currently the research fellow of the Academy of Finland (2007–2012). The research interests of Marja Mikkola include: development and patterning of skin appendages (in particular hair, tooth and mammary gland), role of ectodysplasin and other TNFs in embryogenesis, function of transcription factor p63 in epithelial biology.