Abstract
BackgroundMammary gland development culminates in lactation and is orchestrated by numerous stimuli and signaling pathways. The Src family of nonreceptor tyrosine kinases plays a pivotal role in cell signaling. In order to determine if Src plays a role in mammary gland development we have examined mammary gland development and function during pregnancy and lactation in mice in which expression of Src has been eliminated.ResultsWe have characterized a lactation defect in the Src-/- mice which results in the death of over 80% of the litters nursed by Src-/- dams. Mammary gland development during pregnancy appears normal in these mice; however secretory activation does not seem to occur. Serum prolactin levels are normal in Src-/- mice compared to wildtype controls. Expression of the prolactin receptor at both the RNA and protein level was decreased in Src-/- mice following the transition from pregnancy to lactation, as was phosphorylation of STAT5 and expression of milk protein genes. These results suggest that secretory activation, which occurs following parturition, does not occur completely in Src-/- mice. Failed secretory activation results in precocious involution in the mammary glands of Src-/- even when pups were suckling. Involution was accelerated following pup withdrawal perhaps as a result of incomplete secretory activation. In vitro differentiation of mammary epithelial cells from Src-/- mice resulted in diminished production of milk proteins compared to the amount of milk proteins produced by Src+/+ cells, indicating a direct role for Src in regulating the transcription/translation of milk protein genes in mammary epithelial cells.ConclusionSrc is an essential signaling modulator in mammary gland development as Src-/- mice exhibit a block in secretory activation that results in lactation failure and precocious involution. Src appears to be required for increased expression of the prolactin receptor and successful downstream signaling, and alveolar cell organization.
Highlights
Mammary gland development culminates in lactation and is orchestrated by numerous stimuli and signaling pathways
Src is an essential signaling modulator in mammary gland development as Src-/- mice exhibit a block in secretory activation that results in lactation failure and precocious involution
Mechanisms that may underlie the delay in ductal elongation include changes in estrogen receptor signaling or a change in the amount of estrogen receptor [31], or a requirement for expression of Src in the stromal cell compartment of the mammary gland (Richert et al, unpublished data). While conducting these studies we observed that Src-/- mice display many aspects of a lactation failure including death of most of the pups and retarded growth of any surviving pups. In this manuscript we report that Src is required for the induction of lactation and Src-/- mice exhibit a block in secretory activation that results in lactation failure, death of newborn pups, and precocious involution
Summary
Mammary gland development culminates in lactation and is orchestrated by numerous stimuli and signaling pathways. While the molecular mechanisms underlying secretory activation remain obscure, the expression of several signaling molecules and transcription factors increases at this time, including Src (Richert et al, unpublished data), Akt [7,8,15], Elf5 [16], and sterol response element binding protein (SREBP) [7,8]. Each of these factors may play either unique or redundant roles in secretory activation. Upon weaning of the pups, the mammary gland undergoes involution: involution is characterized by the apoptosis of the majority of the mammary epithelial cells and degradation/remodeling of the extracellular matrix by matrix metalloproteases (MMPs) resulting in ductal structures that closely resemble those present in the virgin mouse [20]
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