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Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes

Institute of Biotechnology, Developmental Biology Program, University of Helsinki, 00014, Helsinki, Finland.
Developmental Biology (Impact Factor: 3.64). 05/2008; 320(1):60-71. DOI: 10.1016/j.ydbio.2008.04.023
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ABSTRACT The development of epithelial appendages, including hairs, glands and teeth starts from ectodermal placodes, and is regulated by interplay of stimulatory and inhibitory signals. Ectodysplasin-A1 (Eda-A1) and Wnts are high in hierarchy of placode activators. To identify direct targets of ectodysplasin pathway, we performed microarray profiling of genes differentially regulated by short exposure to recombinant Eda-A1 in embryonic eda(-/-) skin explants. Surprisingly, there were only two genes with obvious involvement in Wnt pathway: dkk4 (most highly induced gene in the screen), and lrp4. Both genes colocalized with Eda-A1 receptor Edar in placodes of ectodermal organs. They were upregulated upon Edar activation while several other Wnt associated genes previously suggested as Edar targets were unaffected. However, low dkk4 and lrp4 expression was retained in the absence of NF-kappaB signalling in eda(-/-) hair placodes. We provide evidence that this expression was dependent on Wnt activity present prior to Eda-A1/Edar signalling. Dkk4 was recently suggested as a key Wnt antagonist regulating lateral inhibition essential for correct patterning of hair follicles. Several pieces of evidence suggest Lrp4 as a Wnt inhibitor, as well. The finding that Eda-A1 induces placode inhibitors was unexpected, and underlines the importance of delicate fine-tuning of signalling during placode formation.

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Available from: Sylvie Lefebvre, Apr 08, 2014
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    • "Reciprocal interaction between the Wnt/β-catenin and Eda/Edar/NF-κB signaling pathways continues throughout the process of ectodermal organ development. In developing skin appendages, Dkk4, which acts as an inhibitor of Wnt signaling, is the direct transcriptional target of Eda/Edar signaling during placode formation [39]. Zhang et al. recently showed a sequential interdependency between the Wnt and Eda pathways in developing hair follicles: Wnt/β-catenin signaling is essential for NF-κB activation, whereas Edar/NF-κB is thereafter required to strengthen and maintain Wnt/β-catenin activity [13]. "
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    • "Classical tissue recombination experiments suggested that the condensing dermis carries the initial signal, inducing hair placode formation in the overlying epidermis (Dhouailly, 1973). However, more recent work has shown the existence of epidermal to dermal communication from the earliest stages of hair placode patterning, as well as the very early patterned expression of epidermal hair placode markers in the absence of dermal condensation (Fliniaux et al., 2008; Mou et al., 2006; Huh et al., 2013). These findings suggest a transfer of instructive information from epidermis to dermis at a very early stage of hair follicle induction. "
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    • "DKK4 is an Eda-A1/Edar target gene [9] and is transiently expressed in the epidermis in pre-placodal locations ([2]; Fig. 6c). DKK expression affects placode size and hair spacing [2, 9, 35]. Due to reduced Wnt signalling and consequent reduced Eda expression, placode size and hair spacing would thus be expected to be perturbed in Wnt1-cre(+/−)::Pygo(−/−) mice, which is in agreement with our observations. "
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