AbstractsBiology & Animal Science

Molecular regulation of embryonic mammary gland development

by Maria Voutilainen

Institution: University of Helsinki
Department: Department of Biosciences, Genetics; Institute of Biotechnology, University of Helsinki
Year: 2015
Keywords: kehitysbiologia/perinnöllisyystiede
Record ID: 1136050
Full text PDF: http://hdl.handle.net/10138/153040


Mammary gland development begins during embryogenesis with the formation of species-typical number of mammary placodes that emerge along the flanks of the embryo at conserved positions. By birth, the mammary primordium has undergone branching morphogenesis and displays a small ductal tree with several branches. The organ development and growth continues throughout postnatal life and the mammary gland matures to functional form only during pregnancy and following lactation. Ectodysplasin (Eda), a member of the tumour necrosis factor family, is one of the key regulators of epithelial appendage development in all vertebrates. In humans, mutations in the Eda gene, or in other components of the signalling pathway, cause hypohidrotic ectodermal dysplasia (HED), a disorder characterized by sparse hair, missing teeth, and defects in several exocrine glands including the breast. Previous studies have shown that transgenic overexpression of Eda (K14-Eda mice) in the developing ectoderm leads to formation of ectopic mammary placodes, which give rise to supernumerary glands in the adult mice. Otherwise, effects of Eda signalling in the mammary gland have been fairly unknown. Here I have analysed the role of Eda in prepubertal mammary gland development. Characterization of the mammary glands of Eda gain- (K14-Eda) and loss-of-function (Eda−/−) mice revealed that the branching morphogenesis of the organs correlated with Eda levels. Overexpression of Eda induced precocious and accelerated branching whereas lack of Eda reduced number of ductal tips. Furthermore, Eda induced supernumerary mammary placode formation not only on the flank but also in the neck region. Analysis of the mouse line with suppressed NF-kappaB signaling (IκBαΔN mice) revealed that the transcription factor is a major mediator of Eda in the mammary gland. NF-kappaB activity was shown to be necessary for the ability of Eda to induce supernumerary mammary primordia and to accelerate branching morphogenesis. With a candidate gene approach and genome wide-profiling several potent Eda target genes were identified in the mammary gland. Among them were members of the Wnt/beta-cat pathway. The obtained results suggest that Eda promotes mammary cell fate by enhancing canonical Wnt pathway activity and other effects of Eda are cooperatively mediated by certain Wnt family members in addition to other factors. To study mammary placode formation and branching morphogenesis and to assess roles of individual downstream factors or pathways, ex vivo culture systems were developed and utilized in this thesis work. Rinta- eli maitorauhaset ovat nisäkkäiden määrittelevimpiä piirteitä. Niissä tuotettu maito erittyy nännien eli nisien kautta jälkeläiselle. Tästä tulee myös nimi nisäkäs. Rinnat muodostuvat haaroittuneesta maitorauhasesta ja sitä ympäröivästä rasvakudoksesta. Niiden kehitys alkaa jo ennen syntymää. Tällöin sikiön molempien kylkien ihoon muodostuvat maitojuosteiksi kutsutut alueet, jotka ulottuvat kainaloista nivusiin. Kehityksen edetessä rakenteet häviävät, mutta…