DC-SCRIPT deficiency delays mouse mammary gland development and branching morphogenesis

Prep1 (pKnox1) is a homeodomain transcription factor essential for in utero and post-natal development and an oncosuppressor gene in human and adult mice. We have analyzed its role in the development of the mouse mammary gland. We used Prep1i/i hypomorphic and Prep1F/F-Ker5CRE crosses to analyze the role of Prep1 in vivo in adult mouse mammary gland development. We also cultured mammary gland stem/progenitor cells in mammospheres to perform biochemical studies. Prep1 was expressed in mammary gland progenitors and fully differentiated mammary gland cells. Using different Prep1-deficient mouse models we show that in vivo Prep1 contributes to mammary gland branching since the branching efficiency of the mammary gland in Prep1-deleted or Prep1 hypomorphic mice was largely reduced. In-vitro, Prep1 sustained functions of the mammary stem/progenitor compartment. Prep1-deficient mammary stem/progenitor cells showed reduced ability to form mammospheres; they were not able to branch in a 3D assay, and exhibited reduced expression of Snail1, Snail2 and vimentin. The branching phenotype associated with increased Tp53-dependent apoptosis and inability to properly activate signals involved in branching morphogenesis. Finally, Prep1 formed complexes with Snail2, a transcription factor essential in branching morphogenesis, and its absence destabilizes and promotes Snail2 proteasome-mediated degradation. We conclude that Prep1 is required for normal adult mammary gland development, in particular at its branching morphogenesis step. By binding Snail2, Prep1 protects it from the proteasomal degradation.

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Expression of Terminal Differentiation Proteins Defines Stages of Mouse Mammary Gland Development

Veterinary Pathology ◽

10.1354/vp.43-1-36 ◽

2006 ◽

Vol 43 (1) ◽

pp. 36-49 ◽

Cited By ~ 44

Author(s):

I. Mikaelian ◽

M. Hovick ◽

K. A. Silva ◽

L. M. Burzenski ◽

L. D. Shultz ◽

...

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Terminal Differentiation ◽

Mouse Mammary Gland ◽

Gland Development

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In vivo and in vitro evidence of basic fibroblast growth factor action in mouse mammary gland development

FEBS Letters ◽

10.1016/s0014-5793(98)01370-2 ◽

1998 ◽

Vol 439 (3) ◽

pp. 351-356 ◽

Cited By ~ 10

Author(s):

Sergio Lavandero ◽

Andrés Chappuzeau ◽

Mario Sapag-Hagar ◽

Takami Oka

Keyword(s):

Mammary Gland ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Mammary Gland Development ◽

Mouse Mammary Gland ◽

Fibroblast Growth ◽

Gland Development

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Landscape of genomic imprinting and its functions in the mouse mammary gland

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa020 ◽

2020 ◽

Author(s):

Haibo Xu ◽

Lina Zhao ◽

Xu Feng ◽

Yujie Ma ◽

Wei Chen ◽

...

Keyword(s):

Mammary Gland ◽

Genomic Imprinting ◽

Growth Regulation ◽

Mammary Gland Development ◽

Epigenetic Modification ◽

Meta Analysis ◽

Mouse Mammary Gland ◽

Sequencing Data ◽

Functional Studies ◽

Gland Development

Abstract Genomic imprinting is an epigenetic modification of DNA, whereby gene expression is restricted to either maternally or paternally inherited alleles. Imprinted genes (IGs) in the placenta and embryo are essential for growth regulation and nutrient supply. However, despite being an important nutrition delivery organ, studies on mammary gland genomic imprinting remain limited. In this study, we found that both the number of IGs and their expression levels decreased during development of the mouse mammary gland. IG expression was lineage-specific and related to mammary gland development and lactation. Meta-analysis of single-cell RNA sequencing data revealed that mammary gland IGs were co-expressed in a network that regulated cell stemness and differentiation, which was confirmed by our functional studies. Accordingly, our data indicated that IGs were essential for the self-renewal of mammary gland stem cells and IG decline was correlated with mammary gland maturity. Taken together, our findings revealed the importance of IGs in a poorly studied nutrition-related organ, i.e. the mammary gland, thus providing a reference for further studies on genomic imprinting.

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Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle in mice

Reproduction Fertility and Development ◽

10.1071/rd19378 ◽

2020 ◽

Vol 32 (8) ◽

pp. 774

Author(s):

Vahid Atashgaran ◽

Pallave Dasari ◽

Leigh J. Hodson ◽

Andreas Evdokiou ◽

Simon C. Barry ◽

...

Keyword(s):

Transcription Factor ◽

Mammary Gland ◽

Mammary Gland Development ◽

Cancer Susceptibility ◽

Branching Morphogenesis ◽

Genetic Mutation ◽

Oestrous Cycle ◽

Normal Mammary Gland ◽

Foxp3 Mrna ◽

Gland Development

Female mice heterozygous for a genetic mutation in transcription factor forkhead box p3 (Foxp3) spontaneously develop mammary cancers; however, the underlying mechanism is not well understood. We hypothesised that increased cancer susceptibility is associated with an underlying perturbation in mammary gland development. The role of Foxp3 in mammary ductal morphogenesis was investigated in heterozygous Foxp3Sf/+ and wildtype Foxp3+/+ mice during puberty and at specific stages of the oestrous cycle. No differences in mammary ductal branching morphogenesis, terminal end bud formation or ductal elongation were observed in pubertal Foxp3Sf/+ mice compared with Foxp3+/+ mice. During adulthood, all mice underwent normal regular oestrous cycles. No differences in epithelial branching morphology were detected in mammary glands from mice at the oestrus, metoestrus, dioestrus and pro-oestrus stages of the cycle. Furthermore, abundance of Foxp3 mRNA and protein in the mammary gland and lymph nodes was not altered in Foxp3Sf/+ mice compared with Foxp3+/+ mice. These studies suggest that Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle. Further studies are required to dissect the underlying mechanisms of increased mammary cancer susceptibility in Foxp3Sf/+ heterozygous mice and the function of this transcription factor in normal mammary gland development.

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