Lobuloalveolar development was severely impaired from early pregnancy ( Fig.
We collected Elf5 −/− mammary transplants during pregnancy ( Fig. ( C) Representative Western blot of phosphorylated Erk (pErk) and Erk (Erk) protein levels in Elf5 −/− and wild-type mammary transplants at 4.5 dpc. ( B) The percentage of cells stained positive for an antibody against the proliferation antigen Ki67 in mammary transplants with wild type (black bars) and Elf5 −/− (white bars) epithelium collected at 4.5 and 6.5 dpc. Low-power ( bottom) and high-power ( top left) whole-mounts and mammary epithelium stained with an antibody against milk proteins (brown, top right) counterstained with haematoxylin are illustrated. ( A) Mammary gland morphology from wild-type ( left panels) and Elf5 −/− ( right panels) mammary transplants collected from virgin ( top third), 12.5-dpc ( middle third), and 1-d-post-partum ( bottom third) hosts. Thus loss of Elf5 did not affect the proportion or self-renewal capacity of MaSCs or the process of ductal morphogenesis.ĭeletion of Elf5 results in failed alveolar differentiation. Transplantation at limiting dilution revealed that Elf5 −/− MaSCs had a similar repopulating potential to wild-type MaSCs (data not shown). 2006) compared with control mammary transplants (wild type). FACS analysis of freshly isolated epithelial cells (Lin −) from Elf5 −/− mammary transplants revealed no difference in the proportion of CD24 +CD29 hi double-positive cells enriched for mammary stem cells (MaSCs) ( Shackleton et al. More than 95% of transplants successfully engrafted, and all that did so displayed normal ductal elongation, bifurcation, and side-branching ( Fig. 2005), and post-pubertal Elf5 −/− mammary epithelium was serially transplanted to wild-type Rag1 −/− hosts. Here we show that Elf5 is essential for normal alveolar development and lactation due to regulation of the CD61 + progenitor cell population, establishing the links between hormonal regulation, gene expression, progenitor cell activity, and biological function that result in milk being available to the neonate.Įlf5 is essential for the differentiation phase of alveolar development during pregnancyĮlf5-null ( Elf5 −/−) embryos were generated by tetraploid embryonic stem (ES) cell rescue to avoid the placentation defect ( Donnison et al. Elf5 can trans-activate the whey acidic protein (Wap) promoter, a component of milk ( Thomas et al. Retroviral re-expression of Elf5 in Prlr knockout mammary glands rescued alveolar morphogenesis in a dose-dependent fashion ( Harris et al. Elf5 heterozygote mice ( Elf5 +/−) show defective lobuloalveolar development and reduced milk secretion during pregnancy ( Zhou et al. Elf5 is required for placentation, and as a consequence the knockout ( Elf5 −/−) conceptus is nonviable by day 7.5–8.5 of pregnancy ( Donnison et al. Gata3 is essential for ductal and alveolar morphogenesis via regulation of the stem and CD61 + progenitor cell pools ( Kouros-Mehr et al. 1999) and Gata3 may lie downstream from the prolactin receptor ( Ormandy et al.
We showed previously that the transcription factors Elf5 ( Zhou et al. The precise location, arrangement, composition, and regulation of these programs is the subject of intense interest ( Kordon and Smith 1998 Smalley and Ashworth 2003 Shackleton et al. These cues initiate interacting programs of altered gene expression, cell division, and differentiation within the stem and progenitor cell hierarchy. Mammary morphogenesis occurs predominantly after birth and is coordinated with reproductive events by shared hormonal cues ( Neville et al.
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