Mcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling

Xing Yang, Haibo Xu, Xu Yang, Hui Wang, Li Zou, Qin Yang, Xiaopeng Qi, Li Li, Hongxia Duan, Xiyun Yan, Nai Yang Fu, Jing Tan (), Zongliu Hou () and Baowei Jiao ()
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Xing Yang: Yan’an Hospital Affiliated to Kunming Medical University
Haibo Xu: Chinese Academy of Sciences
Xu Yang: Chinese Academy of Sciences
Hui Wang: Chinese Academy of Sciences
Li Zou: Chinese Academy of Sciences
Qin Yang: Chinese Academy of Sciences
Xiaopeng Qi: Chinese Academy of Sciences
Li Li: Chinese Academy of Sciences
Hongxia Duan: Chinese Academy of Sciences
Xiyun Yan: Chinese Academy of Sciences
Nai Yang Fu: Duke-NUS Medical School
Jing Tan: Yan’an Hospital Affiliated to Kunming Medical University
Zongliu Hou: Yan’an Hospital Affiliated to Kunming Medical University
Baowei Jiao: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract While canonical Wnt signaling is well recognized for its crucial regulatory functions in cell fate decisions, the role of non-canonical Wnt signaling in adult stem cells remains elusive and contradictory. Here, we identified Mcam, a potential member of the non-canonical Wnt signaling, as an important negative regulator of mammary gland epithelial cells (MECs) by genome-scale CRISPR-Cas9 knockout (GeCKO) library screening. Loss of Mcam increases the clonogenicity and regenerative capacity of MECs, and promotes the proliferation, differentiation, and ductal morphogenesis of mammary epithelial in knockout mice. Mechanically, Mcam knockout recruits and polarizes macrophages through the Il4-Stat6 axis, thereby promoting secretion of the non-canonical Wnt ligand Wnt5a and its binding to the non-canonical Wnt signaling receptor Ryk to induce the above phenotypes. These findings reveal Mcam roles in mammary gland development by orchestrating communications between MECs and macrophages via a Wnt5a/Ryk axis, providing evidences for non-canonical Wnt signaling in mammary development.

Date: 2024
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DOI: 10.1038/s41467-023-44338-0

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