Abstract
Mammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary gland fuel the morphogenesis and regeneration of a complex epithelial network during development and upon transplantation. The self-renewal of basal stem/progenitor cells is subjected to regulation by both cell-intrinsic and extrinsic mechanisms. Nfatc1 is a transcription factor that regulates breast tumorigenesis and metastasis, but its role in mammary epithelial development and stem cell function has not been investigated. Here we show that Nfatc1 is expressed in a small subset of mammary basal epithelial cells and its epithelial-specific deletion results in mild defects in side branching and basal-luminal cell balance. Moreover, Nfatc1-deficient basal cells exhibit reduced colony forming ability in vitro and somewhat compromised regenerative potential upon transplantation. Thus, our study provides evidence for a detectable yet non-essential role of Nfatc1 in mammary epithelial morphogenesis and basal stem/progenitor cell self-renewal.
Highlights
The mammary gland is a dynamic and regenerative organ that undergoes most of its development after birth, with dramatic structural and functional changes occurring during puberty, pregnancy, lactation, and involution
To probe potential Nfatc1 involvement in mammary epithelial morphogenesis, we first interrogated a publicly available microarray dataset on whole mammary gland tissues [19, 20]. This analysis revealed high Nfatc1 expression during early pregnancy that gradually declined by mid-pregnancy and remained low during lactation and involution (Fig. 1a)
At all passages examined, the number of colonies formed in the Nfatc1 mammary epithelial-specific knockout (MSKO) culture was significantly lower than that in the control culture (Fig. 4c). These results suggest that Nfatc1 likely regulates the self-renewal capacity of mammary basal stem/progenitor cells, rather than the rate of basal cell proliferation per se
Summary
The mammary gland is a dynamic and regenerative organ that undergoes most of its development after birth, with dramatic structural and functional changes occurring during puberty, pregnancy, lactation, and involution. Under the regulation of hormones and local growth factors, stem/progenitor cells in the mammary epithelium self-renew, proliferate, and differentiate to drive the growth, remodeling, and Melissa McNeil and Yingying Han have contributed to this work. The basal compartment houses both unipotent (generating only basal progenies) and multi/bi-potent (generating both basal and luminal progenies) stem cells that fuel morphogenesis and regeneration [1, 5,6,7,8,9]. Despite extensive studies identifying a myriad of molecular and signaling pathways that regulate mammary epithelial stem cell activity and differentiation [1, 6], transcriptional mechanisms underlying mammary epithelial morphogenesis and basal stem cell selfrenewal remain to be fully understood. Nfatc is required for breast cancer cell migration and invasion in vitro as well as tumorigenesis and metastasis in vivo, and its expression is upregulated
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