Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A - PubMed (original) (raw)

Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A

Daisuke Yamaji et al. Genes Dev. 2009.

Abstract

Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B, which mediate cytokine signaling. To reveal the underlying causes for this developmental block, we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and its ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Thus, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Flow cytometry analyses of mammary cells from Stat5a/5bfl/fl mice (left panels) and Stat5a/5bfl/fl;Cre mice (right panels). (A) Dot plot pattern of luminal (Lum; CD24hiCD49flo), myoepithelial (Myo; CD24loCD49fhi) and stem cell-enriched (Stem; CD24midCD49fhi) populations in 12-wk-old virgin mice. (B) CD61 staining histograms of luminal cell population (CD24hiCD49flo) in the mammary gland of 12-wk-old virgin mice (top panels) and 6 d pregnant mice (P6, bottom panels). The CD61+ population was determined according to fluorescence minus one (FMO) control of the same mouse. (C) Bar graph depicting the percentage of CD61+ cells in luminal cell populations of Stat5a/5bfl/fl (blank bars) and Stat5a/5bfl/fl;Cre (filled bars) mammary glands in virgins, and on day 6 (P6) and day 12 (P12) of pregnancy. Values are means ± SD. (*) P < 0.05.

Figure 2.

Figure 2.

Histology of mammary tissue of Stat5a/5bfl/fl;Cre;iStat5 mice in the presence or absence of doxycycline. (A) Schematic design of the experimental protocol. Mice were fed with doxycycline-containing food from mating to the end of the second lactation, and again after delivery of the fourth litter. (B) Mammary glands of Stat5a/5bfl/fl;Cre;iStat5 mice were biopsied on the day of delivering the first (panels a,d), fourth (panels b,e), and sixth (panels c,f) litters and were stained with hematoxylin and eosin (panels a–c) or immunostained with anti-phosphorylated STAT5 antibody (red) and anti-E-cadherin antibodies (green) (panels d–f). Black arrows indicate lumina. White arrows point to cells containing nuclear pSTAT5.

Figure 3.

Figure 3.

Flow cytometry analyses of mammary luminal progenitor cells in the presence or absence of STAT5A/5B. Dot plot patterns of CD24 and CD49f populations and histograms of CD61 staining of luminal cell population in the mammary tissue of mice with indicated genotype 4 wk after weaning. Mammary tissues of Stat5a/5bfl/fl;Cre;iStat5 mice were analyzed with or without feeding doxycycline.

Figure 4.

Figure 4.

Schematic model depicting the role of STAT5A/5B and other transcription factors in the development of mammary epithelial cell lineages. (Top row) In the wild-type mammary gland, epithelial stem cells generate alveolar luminal progenitor cells that develop mature alveoli during pregnancy. (Middle) Alveolar progenitor cells fail to differentiate into secretory luminal cells in the absence of GATA3 or ELF5, leading to their accumulation in pregnancy and lack of alveolar development. (Bottom row) Loss of STAT5A/5B impairs development of alveolar precursor cells (this study) as well as maintenance of mature alveolar cells as shown previously.

References

    1. Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007;9:201–209. - PubMed
    1. Buono KD, Robinson GW, Martin C, Shi S, Stanley P, Tanigaki K, Honjo T, Hennighausen L. The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy. Dev Biol. 2006;293:565–580. - PubMed
    1. Choi YS, Chakrabarti R, Escamilla-Hernandez R, Sinha S. Elf5 conditional knockout mice reveal its role as a master regulator in mammary alveolar development: Failure of Stat5 activation and functional differentiation in the absence of Elf5. Dev Biol. 2009;329:227–241. - PubMed
    1. Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX, Robinson GW, Hennighausen L. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004;24:8037–8047. - PMC - PubMed
    1. Gunther EJ, Belka GK, Wertheim GB, Wang J, Hartman JL, Boxer RB, Chodosh LA. A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology. FASEB J. 2002;16:283–292. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources