Research article

Lactation failure in Src knockout mice is due to impaired secretory activation

Harriet Watkin¹ , Monica M Richert^1,4 , Andrew Lewis¹ , Kristina Terrell¹ , James P McManaman^2,3 and Steven M Anderson¹

¹Department of Pathology, University of Colorado Health Sciences Center, Research Complex I, South Tower, Mail Stop 8104, 12801 East 17th Avenue, Aurora, CO 80045, USA

²Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Research Complex I, South Tower, Mail Stop 8307, 12801 East 17 th Avenue, Aurora, CO 80045, USA

³Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Research Complex I, South Tower, Mail Stop 8309, 12801 East 17 th Avenue, Aurora, CO 80045, USA

⁴Department of Pathology, University of Alabama at Birmingham, Volker Hall, G-038A, 1670 University Blvd, Birmingham, AL 35294, USA

author email corresponding author email

BMC Developmental Biology 2008, 8:6doi:10.1186/1471-213X-8-6

Published:	23 January 2008

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.

Conclusion

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.