The Stat6-regulated KRAB domain zinc finger protein Zfp157 regulates the balance of lineages in mammary glands and compensates for loss of Gata-3

Abstract

Lineage commitment studies in mammary glands have focused on identifying cell populations that display stem or progenitor properties. However, the mechanisms that control cell fate have been incompletely explored. Herein we show that zinc finger protein 157 (Zfp157) is required to establish the balance between luminal alveolar pStat5-and Gata-3-expressing cells in the murine mammary gland. Using mice in which the zfp157 gene was disrupted, we found that alveologenesis was accelerated concomitantly with a dramatic skewing of the proportion of pStat5-expressing cells relative to Gata-3 + cells. This suppression of the Gata-3 + lineage was associated with increased expression of the inhibitor of helix-loop-helix protein Id2. Surprisingly, Gata-3 becomes dispensable in the absence of Zfp157, as mice deficient for both Zfp157 and Gata-3 lactate normally, although the glands display a mild epithelial dysplasia. These data suggest that the luminal alveolar compartment of the mammary gland is comprised of a number of distinct cell populations that, although interdependant, exhibit considerable cell fate plasticity.

Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages

“…However, unlike L-alveolar cells, parity-induced MECs are bona fide alveolar progenitors. Consistent with previous reports 35,36 , our analysis clearly demonstrates the existence of at least two functionally distinct luminal alveolar lineages (that is, L-alveolar and classical secretory luminal alveolar). It remains to be determined whether the transit alveolar population we observed in early pregnancy also represents a functionally distinct luminal alveolar lineage.…”

Mammary stem cells and the differentiation hierarchy: current status and perspectives

“…The reduced pool of luminal progenitor cells accompanying loss of Stat5a suggests a role for this gene in the generation or expansion of alveolar progenitor cells from MaSCs (Yamaji et al 2009). Interestingly, the Stat6-regulated zinc finger protein Zfp157 is required to establish the balance of Gata-3-versus Stat5a-expressing luminal cell subtypes during alveologenesis (Oliver et al 2012). Physiologically, C/EBPb also specifies luminal cell fate in the mammary gland, and its loss induces misexpression of basal markers in the luminal cell compartment (LaMarca et al 2010).…”

KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions

“…The zinc finger protein 157 (zfp157) plays a role in alveologenesis, regulating the balance between luminal alveolar pStat5 and Gata-3 expressing cells in murine mammary glands [78]. …”