How is milk supply built with each pregnancy? by Oscar Cazares

Oscar Cazares

UC Santa Cruz

The breast is a remarkable organ that is capable of building a milk supply with each pregnancy, yet a significant number of women experience lactation insufficiency. My research is focused in understanding how the breast build a milk supply with every pregnancy. My data sugest that Slit/Robo1/β-catenin signaling in basal cells regulates Jag1 expression to govern mammary alveologenesis and milk production by controlling alveolar progenitor differentiation through luminal Notch activity.

ABSTRACT

In the breast, how enduring, lineage-restricted progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 through β-catenin. This reduces Notch signaling in the luminal compartment and promotes lobuloalveolar development. Robo1 loss in mammary epithelial tissue activates Notch signaling, resulting in alveolar progenitor expansion at the expense of lobuloalveolar development. SLITs inhibit ROBO1/β-catenin signaling, thereby activating Notch and reducing alveologenesis. By contrast, loss of Slits or delivery of ROBO1-5Ig-Fc, which sequesters SLITs, increases both lobuloalveolar development and milk production. Thus, targeting the regulatory mechanisms controlling mammary alveolar progenitor cell recruitment and differentiation represents a new approach to therapies for lactation insufficiency, a syndrome that adversely affects women and their children worldwide.

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