Endoplasmic Reticulum Homeostasis In The Mouse Mammary Epithelium During Lactation
Lactation is an essential stage of mammalian life. Milk is a complex fluid that provides complete nutrition for neonates in the early stages of postnatal life. The organic components of milk, such as milk proteins and lipids, are synthesized and secreted by mammary epithelial cells (MEC). A key differentiation event in MEC is the development of an extensive endoplasmic reticulum (ER) network. At the onset of lactation, copious amount of lipid and protein synthesis could perturb the ER luminal environment. However, little is known about ER function in the context of lactation. Professional secretory cells rely on adaptive mechanisms to maintain ER homeostasis including the Unfolded Protein Response (UPR) and elimination of misfolded and improperly modified proteins via the Endoplasmic Reticulum Associated Degradation (ERAD). Two components of the UPR and ERAD, XBP1 and Sel1L respectively, have been implicated in maintaining ER function in secretory cells. However, the roles of XBP1 and Sel1L during lactation have not been investigated. To this end, we specifically ablated XBP1 and Sel1L in MEC during lactation. Our findings indicate that XBP1 is required for sustaining pup growth during lactation. Absence of XBP1 resulted in a severe reduction of the ER compartment and substantially smaller mammary epithelial compartment during lactation. Notably, our findings are the first to directly demonstrate that XBP1 is absolutely necessary for the development and expansion of an extensive ER network in the MEC. In the case of Sel1L, its absence had little impact on lactation, even though the morphology of the ER was abnormal and markers of ER stress were elevated. More importantly, our findings are the first to suggest that Sel1L is dispensable for MEC function. Taken together, our findings provide novel insight of the contribution of the two ER homeostatic systems during the dynamic and metabolically demanding stage of lactation.
endoplasmic reticulum; mammary gland; lactation
Weiss,Robert S.; Qi,Ling; Long,Qiaoming
Ph. D., Animal Science
Doctor of Philosophy
dissertation or thesis