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The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland.

ABSTRACT: The high mobility group-domain containing transcription factor Sox10 is an essential regulator of developmental processes and homeostasis in the neural crest, several neural crest-derived lineages and myelinating glia. Recent studies have also implicated Sox10 as an important factor in mammary stem and precursor cells. Here we employ a series of mouse mutants with constitutive and conditional Sox10 deficiencies to show that Sox10 has multiple functions in the developing mammary gland. While there is no indication for a requirement of Sox10 in the specification of the mammary placode or descending mammary bud, it is essential for both the prenatal hormone-independent as well as the pubertal hormone-dependent branching of the mammary epithelium and for proper alveologenesis during pregnancy. It furthermore acts in a dosage-dependent manner. Sox10 also plays a role during the involution process at the end of the lactation period. Whereas its effect on epithelial branching and alveologenesis are likely causally related to its function in mammary stem and precursor cells, this is not the case for its function during involution where Sox10 seems to work at least in part through regulation of the miR-424(322)/503 cluster.

SUBMITTER: Mertelmeyer S

PROVIDER: S-EPMC7575560 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland.

Mertelmeyer Svenja S Weider Matthias M Baroti Tina T Reiprich Simone S Fröb Franziska F Stolt C Claus CC Wagner Kay-Uwe KU Wegner Michael M

Scientific reports 20201020 1

The high mobility group-domain containing transcription factor Sox10 is an essential regulator of developmental processes and homeostasis in the neural crest, several neural crest-derived lineages and myelinating glia. Recent studies have also implicated Sox10 as an important factor in mammary stem and precursor cells. Here we employ a series of mouse mutants with constitutive and conditional Sox10 deficiencies to show that Sox10 has multiple functions in the developing mammary gland. While ther ...[more]

PMID: 33082503

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Project description:BackgroundThe Bcl-3 protein is an atypical member of the inhibitor of -κB family that has dual roles as a transcriptional repressor and a coactivator for dimers of NF-κB p50 and p52. Bcl-3 is expressed in mammary adenocarcinomas and can promote tumorigenesis and survival signaling and has a key role in tumor metastasis. In this study, we have investigated the role of Bcl-3 in the normal mammary gland and impact on tumor pathology.MethodsWe utilized bcl-3-/- mice to study mammary gland structure in virgins and during gestation, lactation and early involution. Expression of involution-associated genes and proteins and putative Bcl-3 target genes was examined by qRT-PCR and immunoblot analysis. Cell autonomous branching morphogenesis and collagen I invasion properties of bcl-3-/- organoids were tested in 3D hydrogel cultures. The role of Bcl-3 in tumorigenesis and tumor pathology was also assessed using a stochastic carcinogen-induced mammary tumor model.ResultsBcl-3-/- mammary glands demonstrated reduced branching complexity in virgin and pregnant mice. This defect was recapitulated in vitro where significant defects in bud formation were observed in bcl-3-/- mammary organoid cultures. Bcl-3-/- organoids showed a striking defect in protrusive collective fibrillary collagen I invasion associated with reduced expression of Fzd1 and Twist2. Virgin and pregnant bcl-3-/- glands showed increased apoptosis and rapid increases in lysosomal cell death and apoptosis after forced weaning compared to WT mice. Bcl-2 and Id3 are strongly induced in WT but not bcl-3-/- glands in early involution. Tumors in WT mice were predominately adenocarcinomas with NF-κB activation, while bcl-3-/- lesions were largely squamous lacking NF-κB and with low Bcl-2 expression.ConclusionsCollectively, our results demonstrate that Bcl-3 has a key function in mammary gland branching morphogenesis, in part by regulation of genes involved in extracellular matrix invasion. Markedly reduced levels of pro-survival proteins expression in bcl-3 null compared to WT glands 24 h post-weaning indicate that Bcl-3 has a role in moderating the rate of early phase involution. Lastly, a reduced incidence of bcl-3-/- mammary adenocarcinomas versus squamous lesions indicates that Bcl-3 supports the progression of epithelial but not metaplastic cancers.

Dataset Information

The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland.

Publications

The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland.

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