Stimulation of ectodermal organ development by Ectodysplasin-A1

Abstract

Organs developing as ectodermal appendages share similar early morphogenesis and molecular mechanisms. Ectodysplasin, a signaling molecule belonging to the tumor necrosis factor family, and its receptor Edar are required for normal development of several ectodermal organs in humans and mice. We have overexpressed two splice forms of ectodysplasin, Eda-A1 and Eda-A2, binding to Edar and another TNF receptor, Xedar, respectively, under the keratin 14 (K14) promoter in the ectoderm of transgenic mice. Eda-A2 overexpression did not cause a detectable phenotype. On the contrary, overexpression of Eda-A1 resulted in alterations in a variety of ectodermal organs, most notably in extra organs. Hair development was initiated continuously from E14 until birth, and in addition, the transgenic mice had supernumerary teeth and mammary glands, phenotypes not reported previously in transgenic mice. Also, hair composition and structure was abnormal, and the cycling of hairs was altered so that the growth phase (anagen) was prolonged. Both hairs and nails grew longer than normal. Molar teeth were of abnormal shape, and enamel formation was severely disturbed in incisors. Furthermore, sweat gland function was stimulated and sebaceous glands were enlarged. We conclude that ectodysplasin-Edar signaling has several roles in ectodermal organ development controlling their initiation, as well as morphogenesis and differentiation.

Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth

“…During tooth development, the K14 promoter directs expression to the basal layer of epidermis and to oral and dental epithelia (Dassule et al, 2000;Mustonen et al, 2003). Our results show that follistatin regulates the morphogenesis of the dental epithelium.…”

“…The first molar reaches the bud stage at E13, the second molar at E16, and the third molar around birth. Although we do not know the exact time of the initiation of transgene expression in our mice, it is conceivable that it is not later than E13, because the expression of the K14-promoted transgenes was previously reported to start around E12 in the ectoderm (Dassule et al, 2000;Mustonen et al, 2003). Therefore, we assume that the ectopic follistatin expression had started well before the initiation of second molar development in our mice.…”

“…Edar (the receptor of Eda) is expressed in the enamel knot, and interestingly, it is stimulated by activin A, although activin does not induce initial Edar expression (Laurikkala et al, 2002). In K14-Eda transgenic mice, Edar signaling is stimulated in the enamel knots, and the molars are enlarged and supernumerary teeth form (Mustonen et al, 2003). However, the tooth phenotypes in follistatin knockout and K14 -follistatin transgenic mice are completely different from the Eda and Edar mutants and transgenic mice.…”

Identification of the mammary line in mouse by Wnt10b expression

“…This hypothesis was based on (1) the lack of induction of placode numbers 1, 2, 3, and 5 in Fgf10 -/-embryos; (2) the lack of Fgf10 expression in the surface ectoderm or mammary rudiments of wild-type littermates until several days beyond the induction of the mammary placodes; (3) the expression of Fgf10 in the dermamyotome at E10.5; and (4) the knowledge that the dermamyotomal region in the ventral bud of the somites gives rise to the dermis (Sengel, 1976), which in turn is instructive for the differentiation of surface ectoderm to mammary epithelium (Sakakura et al, 1987;Cunha and Hom, 1996;reviewed in Veltmaat et al, 2003). Recently, mice expressing transgenic Eda-A1 under the Keratin14 promoter in the surface ectoderm have been reported to have supernumerary mammary glands along a line on the flank at adulthood (Mustonen et al, 2003). It would now be interesting to analyze the exact location of these supernumerary glands and the embryonic stages of mammary gland development in these mice, to gain more insight in the putative interaction between somitic signals and ectodermal response factors.…”

Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits

“…19,20 Animal models have also suggested that the EDA/EDAR pathway regulates the development of ectodermal derivative. [21][22][23][24][25][26][27][28][29] It is also worth noting that, in studies on human population genetics, a strong signal of positive selection in Asian populations has been observed for the EDAR 370A allele. Specifically, the allele is rare in African and European populations and is associated with a long-ranged uniform haplotype in Asian populations.…”