Lactation Defect with Impaired Secretory Activation in AEBP1-Null Mice

Lei Zhang,Brian K Hall,Oleg Bogachev,Hyo-Sung Ro,Amin Majdalawieh Amin Majdalawieh,Shannon P Reidy,Jo-Ann L Stanton

doi:10.1371/journal.pone.0027795

Lei Zhang, Brian K Hall + Show 5 more

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https://doi.org/10.1371/journal.pone.0027795

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Journal: PLoS ONE	Publication Date: Nov 16, 2011
Citations: 34	License type: CC BY 4.0

Affiliation: Dalhousie University, American University of Sharjah

Abstract

Adipocyte enhancer binding protein 1 (AEBP1) is a multifunctional protein that negatively regulates the tumor suppressor PTEN and IκBα, the inhibitor of NF-κB, through protein-protein interaction, thereby promoting cell survival and inflammation. Mice homozygous for a disrupted AEBP1 gene developed to term but showed defects in growth after birth. AEBP1 −/− females display lactation defect, which results in the death of 100% of the litters nursed by AEBP1 −/− dams. Mammary gland development during pregnancy appears normal in AEBP1 −/− dams; however these mice exhibit expansion of the luminal space and the appearance of large cytoplasmic lipid droplets (CLDs) in the mammary epithelial cells at late pregnancy and parturition, which is a clear sign of failed secretory activation, and accumulation of milk proteins in the mammary gland, presumably reflecting milk stasis following failed secretory activation. Eventually, AEBP1 −/− mammary gland rapidly undergoes involution at postpartum. Stromal restoration of AEBP1 expression by transplanting wild-type bone marrow (BM) cells is sufficient to rescue the mammary gland defect. Our studies suggest that AEBP1 is critical in the maintenance of normal tissue architecture and function of the mammary gland tissue and controls stromal-epithelial crosstalk in mammary gland development.

Highlights

The mammary gland is a self-renewing tissue in which morphological changes and differentiation occur cyclically during menstruation, pregnancy and lactation
Accumulation of milk proteins in the mammary gland, expansion of the luminal space, and the appearance of large cytoplasmic lipid droplets (CLDs) strongly suggest a failure in secretory activation in the AEBP12/2 mammary glands
The ratio of the three classes of mice from heterozygote mating indicated that the litter size of AEBP12/2 mice is about half of the wild-type [15], which suggests that Adipocyte enhancer binding protein 1 (AEBP1) gene disruption affects embryonic development

Summary

Introduction

The mammary gland is a self-renewing tissue in which morphological changes and differentiation occur cyclically during menstruation, pregnancy and lactation. Upon initiation of ovarian hormone secretion, the mammary epithelium enters an accelerated growth phase that leads to extension and branching of the ducts until they reach the limits of the fat pad. At the onset of pregnancy, extensive epithelial cell proliferation occurs, leading to the formation of lobulo-alveolar structures and secretory epithelial differentiation for lactation. The event of involution that follows weaning results in the quenching of milk protein gene expression, collapse of the alveolar structures, removal of endothelial, myoepithelial and secretory luminal epithelial cells by apoptosis, phagocytosis by macrophages, proteolytic degradation of the basement membranes, and replacement of most epithelial cells by adipose tissue [6]

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