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Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy

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Abstract

Hypohidrotic ectodermal dysplasias (HED) are hereditary differentiation disorders of multiple ectodermal structures including the mammary gland. The X-linked form of HED (XLHED) is caused by a lack of the secreted signaling molecule ectodysplasin A1 (EDA1) which is encoded by the gene EDA and belongs to the tumor necrosis factor (TNF) superfamily. Although male patients (hemizygous) are usually more severely affected by XLHED, heterozygous female carriers of an EDA mutation may also suffer from a variety of symptoms, in particular from abnormal development of their breasts. In Tabby mice, a well-studied animal model of XLHED, EDA1 is absent. We investigated the effects of prenatal administration of Fc-EDA, a recombinant EDA1 replacement protein, on mammary gland development in female Tabby mice. Intra-amniotic delivery of Fc-EDA to fetal animals resulted later in improved breastfeeding and thus promoted the growth of their offspring. In detail, such treatment led to a normalization of the nipple shape (protrusion, tapering) that facilitated sucking. Mammary glands of treated female Tabby mice also showed internal changes, including enhanced branching morphogenesis and ductal elongation. Our findings indicate that EDA receptor stimulation during development has a stable impact on later stages of mammary gland differentiation, including lactation, but also show that intra-amniotic administration of an EDA1 replacement protein to fetal Tabby mice partially corrects the mammary gland phenotype in female adult animals.

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Acknowledgements

The authors thank Elisabeth Koppmann and Ida Allabauer for excellent technical assistance.

Funding

This work was supported by a grant from the ELAN program of the University Hospital Erlangen (13–12–02-1), grants of the Swiss National Science Foundation and by project funding from Edimer Pharmaceuticals.

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Loschgestr. 15, 91054, Erlangen, Germany

    Mandy Wahlbuhl, Angela Dick, Fabian B. Fahlbusch & Holm Schneider

  2. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

    Sonia Schuepbach-Mallepell, Christine Kowalczyk-Quintas & Pascal Schneider

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  1. Mandy Wahlbuhl
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Correspondence to Mandy Wahlbuhl.

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P.S. is a shareholder of Edimer Pharmaceuticals. P.S. and H.S. hold patents relevant to this publication. The other authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Fig. 1

Hormone-related alterations in Tabby mammary glands. Relative gene expression of RANKL, its receptor RANK, and the hormone receptors for progesterone (PGR), estrogen (ESR1) and prolactin (PRLR) in Tabby (black bars), Fc-EDA-treated Tabby (white bars) and wild-type (striped bars) mammary gland tissue at day L1, as measured by quantitative RT-PCR. Data are shown as mean ± SEM; P-values: not significant (p > 0.05). (PNG 57 kb)

High Resolution Image (TIF 3104 kb)

Supplementary Fig. 2

Nipple morphology scores. Representative example of (a) flat (score 1) (b) cubical (score 2) and (c) cylindrical nipples (score 3) of female mice on day 1 of lactation (L1). (PNG 450 kb)

High Resolution Image (TIF 1385 kb)

Supplementary Fig. 3

Epithelial tight junction barrier. (a-c) Immunostaining for the tight junction protein occludin (red) in mammary glands from untreated Tabby, Fc-EDA-treated Tabby and wild-type mice on day L1. Cell nuclei were stained blue with DAPI. The scale bar in a-c represents 50 μm. (PNG 644 kb)

High Resolution Image (TIF 2992 kb)

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Wahlbuhl, M., Schuepbach-Mallepell, S., Kowalczyk-Quintas, C. et al. Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy. J Mammary Gland Biol Neoplasia 23, 125–138 (2018). https://doi.org/10.1007/s10911-018-9399-x

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