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TRAF6-deficient mice display hypohidrotic ectodermal dysplasia
Asuka Naito1, Hisahiro Yoshida, Eri Nishioka
1Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Abstract:
Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that links signals from members of the TNFR superfamily and Toll/IL-1 receptor family to activation of transcription factors NFkappaB and AP-1. Analysis of TRAF6-deficient mice revealed that TRAF6 is essential for normal bone formation and establishment of immune and inflammatory systems. Here we report that TRAF6 deficiency results in defective development of epidermal appendixes, including guard hair follicles, sweat glands, sebaceous glands of back skin, and modified sebaceous glands such as meibomian glands, anal glands, and preputial glands. Except the sebaceous gland impairment, these abnormal phenotypes are identical to those observed in Tabby (Ta), downless (dl), and crinkled (cr) mice, which are models of hypohidrotic (anhidrotic) ectodermal dysplasia in human. beta-catenin and mucosal addressin cell adhesion molecule-1, an early marker of developing guard-hair follicles is absent in the skin of TRAF6-deficient embryos. Thus, TRAF6 is essential for development of epidermal appendixes. TRAF6 does not associate with the cytoplasmic tail of the dl protein (DL)/ectodysplasin receptor (EDAR) receptor, which, when mutated, results in hypohidrotic (anhidrotic) ectodermal dysplasia. However, TRAF6 associates with X-linked ectodysplasin-A2 receptor (XEDAR) and TNFR super family expressed on the mouse embryo (TROY/toxicity and JNK inducer (TAJ), which are EDAR-related members of the TNFR superfamily that are expressed at high level in epidermal appendixes. Furthermore, TRAF6 is essential for the XEDAR-mediated NFkappaB activation. Our results suggest that TRAF6 may transduce signals emanating from XEDAR or TROY/TAJ that are associated with development of epidermal appendixes.
Insights
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial for developing skin structures like hair follicles and glands. TRAF6 deficiency causes defects in these epidermal appendages, similar to human ectodermal dysplasia.
Area of Science:
- Developmental biology
- Molecular biology
- Immunology
Background:
- Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is a key adapter protein mediating signals from TNFR and Toll/IL-1 receptor families.
- TRAF6 is known to be essential for bone formation and immune/inflammatory system development.
- Previous studies highlighted TRAF6's role in various biological processes, but its specific function in epidermal development was less understood.
Purpose of the Study:
- To investigate the role of TRAF6 in the development of epidermal appendages.
- To identify the specific epidermal structures affected by TRAF6 deficiency.
- To elucidate the molecular mechanisms by which TRAF6 influences epidermal development, particularly its interaction with relevant receptors.
Main Methods:
- Analysis of TRAF6-deficient mice to observe developmental phenotypes.
- Histological examination of skin tissues from TRAF6-deficient embryos.
- Investigation of protein-protein interactions between TRAF6 and members of the TNFR superfamily, including XEDAR and TROY/TAJ.
- Assessment of NF-kappaB activation pathways in relation to TRAF6 and receptor signaling.
Main Results:
- TRAF6 deficiency leads to defective development of epidermal appendages, including hair follicles, sweat glands, and various sebaceous glands.
- These defects mirror phenotypes observed in mouse models of hypohidrotic ectodermal dysplasia.
- Key developmental markers like beta-catenin and mucosal addressin cell adhesion molecule-1 were absent in TRAF6-deficient embryos.
- TRAF6 was found to associate with XEDAR and TROY/TAJ, but not EDAR.
- TRAF6 is essential for XEDAR-mediated NF-kappaB activation.
Conclusions:
- TRAF6 plays an indispensable role in the development of epidermal appendages.
- TRAF6 signaling, potentially through XEDAR or TROY/TAJ, is critical for epidermal development.
- The findings suggest TRAF6's involvement in pathways relevant to ectodermal dysplasia.