title: Lactation failure in Src knockout mice is due to impaired secretory activation.
abstract: BACKGROUND
  Mammary 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  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. Src appears to be required for increased expression of the prolactin receptor and successful downstream signaling, and alveolar cell organization.
authors.affiliation: Department of Pathology, University of Colorado Health Sciences Center, Research Complex I, South Tower, Mail Stop 8104, 12801 East 17th Avenue, Aurora, CO 80045, USA. harriet.watkin@uchsc.edu
authors.forename: Harriet
authors.initials: H
authors.lastname: Watkin
authors.forename: Monica M
authors.initials: MM
authors.lastname: Richert
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewis
authors.forename: Kristina
authors.initials: K
authors.lastname: Terrell
authors.forename: James P
authors.initials: JP
authors.lastname: McManaman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000833:Animals, Suckling / Q000254:growth & development; D002364:Caseins / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D007774:Lactation / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011388:Prolactin / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D015430:Weight Gain; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D002364:Caseins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D011388:Prolactin; D019061:src-Family Kinases