Abstract
X-linked hypohidrotic ectodermal dysplasia with the cardinal symptoms hypodontia, hypotrichosis and hypohidrosis is caused by a genetic deficiency of ectodysplasin A1 (EDA1). Prenatal EDA1 replacement can rescue the development of skin appendages and teeth. Tabby mice, a natural animal model of EDA1 deficiency, additionally feature a striking kink of the tail, the cause of which has remained unclear. We studied the origin of this phenomenon and its response to prenatal therapy. Alterations in the distal spine could be noticed soon after birth, and kinks were present in all Tabby mice by the age of 4 months. Although their vertebral bones frequently had a disorganized epiphyseal zone possibly predisposing to fractures, cortical bone density was only reduced in vertebrae of older Tabby mice and even increased in their tibiae. Different availability of osteoclasts in the spine, which may affect bone density, was ruled out by osteoclast staining. The absence of hair follicles, a well-known niche of epidermal stem cells, and much lower bromodeoxyuridine uptake in the tail skin of 9-day-old Tabby mice rather suggest the kink being due to a skin proliferation defect that prevents the skin from growing as fast as the skeleton, so that caudal vertebrae may be squeezed and bent by a lack of skin. Early postnatal treatment with EDA1 leading to delayed hair follicle formation attenuated the kink, but did not prevent it. Tabby mice born after prenatal administration of EDA1, however, showed normal tail skin proliferation, no signs of kinking and, interestingly, a normalized vertebral bone density. Thus, our data prove the causal relationship between EDA1 deficiency and kinky tails and indicate that hair follicles are required for murine tail skin to grow fast enough. Disturbed bone development appears to be partially pre-determined in utero and can be counteracted by timely EDA1 replacement, pointing to a role of EDA1 also in osteogenesis.
Highlights
X-linked hypohidrotic ectodermal dysplasia (XLHED; #MIM 305100), a rare hereditary disease characterized by missing or dysplastic skin appendages and teeth, is caused by deficiency of the signaling protein ectodysplasin A1 (EDA1) during early development (Mikkola and Thesleff, 2003)
Because the EDA1 pathway is known to interact with the RANKL/RANK signaling pathway (Figure 3B) that plays an important role in osteoclastogenesis (Wada et al, 2006)
The results of our prenatal rescue experiment indicate that reduced bone density is only seen in aged EDA1-deficient mice, it may already be predetermined in utero and, if not, is at least counteracted by something that can be induced by timely EDA1 replacement
Summary
X-linked hypohidrotic ectodermal dysplasia (XLHED; #MIM 305100), a rare hereditary disease characterized by missing or dysplastic skin appendages and teeth, is caused by deficiency of the signaling protein ectodysplasin A1 (EDA1) during early development (Mikkola and Thesleff, 2003). Mutations in the genes EDA1 receptor (EDAR) or EDARADD which underlie genetic deficiencies of the EDAR and its associated death domain-containing adaptor protein, respectively, lead to autosomal recessive or dominant hypohidrotic ectodermal dysplasia. Since all three proteins are part of the EDA1 pathway to nuclear factor (NF)-κB activation, the phenotypic features are similar (Cluzeau et al, 2011). They include hypotrichosis, oligo- or anodontia, and hypoor anhidrosis. The latter is the most severe disability as it can lead to life-threatening hyperthermia on summer days, during physical activity or febrile illness. This significantly increases the childhood mortality (Blüschke et al, 2010)
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