A junction-dependent mechanism drives murine mammary cell intercalation for ductal elongation.

The luminal epithelium of the mammary gland is organized into monolayers; however, it originates from multilayered terminal end buds (TEBs) during development. Although apoptosis provides a plausible mechanism for cavitation of the ductal lumen, it doesn't account for ductal elongation behind TEBs. Spatial calculations in mice suggest that most TEB cells integrate into the outermost luminal layer to generate elongation. We developed a quantitative cell culture assay that models intercalation into epithelial monolayers. We found that tight junction proteins play a key role in this process. ZO-1 puncta form at the new cellular interface and resolve into a new boundary as intercalation proceeds. Deleting ZO-1 suppresses intercalation both in culture and in cells transplanted into mammary glands via intraductal injection. Cytoskeletal rearrangements at the interface are critical for intercalation. These data identify luminal cell rearrangements necessary for mammary development and suggest a mechanism for integration of cells into an existing monolayer.

Id1 Ablation Protects Hematopoietic Stem Cells from Stress-Induced Exhaustion and Aging.

Defining mechanisms that maintain tissue stem cells during homeostasis, stress, and aging is important for improving tissue regeneration and repair and enhancing cancer therapies. Here, we show that Id1 is induced in hematopoietic stem cells (HSCs) by cytokines that promote HSC proliferation and differentiation, suggesting that it functions in stress hematopoiesis. Genetic ablation of Id1 increases HSC self-renewal in serial bone marrow transplantation (BMT) assays, correlating with decreases in HSC proliferation, mitochondrial biogenesis, and reactive oxygen species (ROS) production. Id1-/- HSCs have a quiescent molecular signature and harbor less DNA damage than control HSCs. Cytokines produced in the hematopoietic microenvironment after γ-irradiation induce Id1 expression. Id1-/- HSCs display a blunted proliferative response to such cytokines and other inducers of chronic proliferation including genotoxic and inflammatory stress and aging, protecting them from chronic stress and exhaustion. Thus, targeting Id1 may be therapeutically useful for improving HSC survival and function during BMT, chronic stress, and aging.