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332the location of an ancestral premolar (Kangas et al., 2004; Mustonen et al., 2003).”Und ähnlich noch einmal p. 3193: "K14-Eda mice have a more complex cusppattern in all molars compared with WT mice, and, in addition, ~50% ofindividuals (in the FVB background 644 ) have an extra molar anterior to the firstmolar in the position of an ancestral premolar (Kangas et al., 2004; Mustonen etal., 2003).”Unter Berücksichtigung des gesamten Organismus und nicht nur der isoliertenOrgane und nicht zuletzt der potenzierten Synorganisation aller biochemischenProzesse und anatomischen Strukturen eines Organismus stellt sich die Frage nachdem Selektionswert solcher Veränderungen (angenommen, Ähnliches könnte sichauch in the wild abspielen 645 ). Dafür dürften u. a. folgende Aspekte und Punkterelevant sein. Mustonen et al. 2004, p. 4913 646 :"The finding that only half of these transgenic placodes gave rise to erupted teeth indicates that theremay be a delicate balance of activating and inhibitory influences that determine whether a placodedevelops to a mature tooth or not.”Ganz im Sinne von Häärä et al (2012, p. 3189: "The development of complexstructures requires specific sets of genes to be activated and/or inhibited in acorrect temporal and spatial pattern.”) zeigen Mustonen et al., dass dieÜberexpression von K14-Eda auch nachteilige Wirkungen hat (p. 4908):"[W]e have recently shown that transgenic mice overexpressing the Eda-A1 647 isoform of ectodysplasin(ligand of Edar) under keratin 14 (K14) promoter, which drives the expression to the developing ectodermas early as embryonic day 9 (E9), well before the development of any ectodermal appendage is initiated, arefeatured by supernumerary ectodermal organs (Mustonen et al., 2003). Most notably, these mice have extramammary glands and teeth. Furthermore, hair follicles are produced continuously between E14 andbirth in K14-Eda-A1 mice, unlike in wild-type mice where they develop in three separate wavesgiving rise to the different pelage hair types.” 648Ähnlich Mustonen et al. (2003, p. 123 649 ):"[O]verexpression of Eda-A1 resulted in alterations in a variety of ectodermal organs, most notably in extraorgans. Hair development was initiated continuously from E14 until birth, and in addition, the transgenicmice had supernumerary teeth and mammary glands, phenotypes not reported previously in transgenicmice. Also, hair composition and structure was abnormal, and the cycling of hairs was altered so thatthe growth phase (anagen) was prolonged. Both hairs and nails grew longer than normal. Molar teethwere of abnormal shape, and enamel formation was severely disturbed in incisors.”Einen sehr deutlichen Überblick über die Vielzahl der gestörten Entwicklungender K14-Eda-A1-Mäuse gibt u. a. die "Fig. 2. Eda-A1 overexpression affects the644 Vgl. Taketo et al. (1991): FVB/N: An inbred mouse strain preferable for transgenic analyses. Proc. Natl. Acad. Sci. 88: 2065-2069http://www.pnas.org/content/88/6/2065.full.pdf645 Nicht gerade sehr wahrscheinlich.646 http://dev.biologists.org/content/131/20/4907.full.pdf+html647 Bei Häärä et al. (2012, p. 3819 und im Folgenden) zu Eda abgekürzt ("Eda-A1 (hereafter Eda)")648 Weitere relevante Punkte bei Mustonen et al. 2004, z. B. p. 4915: "Our results from the analysis of Eda-A1-overexpressing mouse embryosindicate that increased signalling via Eda-A1 receptor Edar promotes placodal fate in developing mammary glands and teeth, as well as in thefirst wave of hair follicles that give rise to guard hairs. In particular, the placodes of molar teeth as well as guard hairs were increased in size. Themore thorough analysis of the effects Eda-A1 recombinant protein on hair placodes in organ cultures indicated that the stimulation of placodalfate took place at the expense of interplacode region, as evidenced by the expression patterns of placodal marker genes as well as histology.Clearly, lateral inhibition regulating the size as well as the distance of placodes from one another was relieved. In principle, this could beachieved either by inhibiting the action of molecules that mediate lateral inhibition or by promoting the action of placodal activators. This mayalso account for the other phenomena typical to K14-Eda-A1 mice we have reported earlier, i.e. the continuous development of new hairfollicles abnormally close to the pre-existing ones, and the development of extra teeth and mammary glands (Mustonen et al., 2003)."649 Tuija Mustonen, Johanna Pispa, Marja L. Mikkola, Marja Pummila, Aapo T. Kangas, Leila Pakkasjärvi, Risto Jaatinen, Irma Thesleff (2003):Stimulation of ectodermal organ development by Ectodysplasin-A1http://www.sciencedirect.com/science/article/pii/S001216060300157X ;PDF unter http://ac.els-cdn.com/S001216060300157X/1-s2.0-S001216060300157X-main.pdf?_tid=d4c2236c-bba7-11e2-9c3e-00000aacb35e&acdnat=1368434210_9bf87851a887c0267a84b516e4d4e0ed