Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands

Gui Ma; Ang Gao; Yinan Yang; Yuan He; Xi Zhang; Baotong Zhang; Zhiqian Zhang; Mei Li; Xing Fu; Dan Zhao; Rui Wu; Leilei Qi; Qingxia Hu; Juan Li; Liya Fu; Zhengmao Zhu; Jin-Tang Dong

doi:10.1016/j.jgg.2019.03.003

Volume 46 Issue 3

Mar. 2019

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Article Navigation > Journal of Genetics and Genomics > 2019 > 46(3): 119-131

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Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands

doi: 10.1016/j.jgg.2019.03.003

a
Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
b
Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
c
Ningbo Institute of Medical Sciences, Ningbo, 315020, China

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Corresponding author: E-mail address: j.dong@emory.edu (Jin-Tang Dong)
Received Date: 2019-01-09
Accepted Date: 2019-03-05

Available Online: 2019-03-22

Publish Date: 2019-03-20

Abstract

Abstract

Progesterone (Pg)/progesterone receptor (PR) signaling drives mammary gland side-branching and alveologenesis, but the mechanisms through which Pg/PR signaling functions remain to be clarified. Using in vitro and in vivo models and histological and molecular analyses, we determined the role of Zfhx3 transcription factor in mammary gland development driven by Pg/PR signaling. Postnatal deletion of Zfhx3 in mouse mammary epithelial cells attenuated side-branching morphogenesis and alveologenesis. These effects were undetectable in the absence of Pg/PR signaling. During the estrus cycle, Zfhx3 expression corresponded to that of Pg, being at the highest level at the diestrus stage; Zfhx3 deletion inhibited mammary gland branching more potently at diestrus than estrus stage. Loss of Zfhx3 not only attenuated the expansion of stem/progenitor cells driven by Pg/PR signaling, but also impaired the function of Pg/PR signaling in the transcriptional activation of multiple genes. In addition, Pg/PR signaling significantly expanded PR- and Zfhx3-positive epithelial cells, and induced the physical association of ZFHX3 with PR. These findings establish Zfhx3 as an integral transcription factor of Pg/PR signaling in driving side-branching and alveologenesis during mammary gland development.
- Mammary gland,
- Pregnancy,
- Ductal side-branching,
- Alveologenesis,
- Progesterone-progesterone receptor signaling

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