A loss of function mutation was introduced into the PR gene locus in the mouse germ-line using gene targeting (homologous recombination)/ embryonic stem cell techniques. Among the different reproductive phenotypes that resulted from removal of PR function in the homozygote female (-/-) was the inability to generate a lobuloalveolar system within the mammary gland in response to estrogen (E) and progesterone (P) as compared to their wild type littermates (+/+).
Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, Shyamala G, Conneely OM, and OíMalley BW. (1995) Genes & Development 9: 2266-2278.
Brisken et al., 1998) A paracrine role for the epithelial progesterone receptor in
mammary gland development.
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Because of the close temporal and spatial overlap in functional activities attributed to E and P, it has been difficult to directly interpret the influence of P in mammary gland development without also considering the extent of the Eís role. To circumvent this problem and to directly study the role of PR function in mammary gland development and tumorigenesis, a novel mutant mouse strain carrying a germ-line mutation at the PR locus was generated.
Although in the absence of E and P, age matched PR mutants and wild types do not exhibit discernible differences in the adult virgin mammary phenotype, following daily administration of 1ug of E and 1mg of P for three weeks, comparative whole mount analysis revealed striking morphologic differences between the wild type (+/+) and PR mutant (-/-). In the case of the wild type (Panels A and C), in response to this hormonal regimen, extensive ductal branching and full lobuloalveolar development is achieved. In contrast, under the same treatment, the PR mutant (-/-) (Panels B and D) exhibits limited ductal arborization and an inability to produce alveoli bodies, compare panels E and F.
The PR gene targeting vector contained 7kb of the mouse (129SvEv) PR gene that encompassed both the first and second exons. The engineered mutation consisted of the insertion of a neomycin resistance gene into the first exon and downstream from the initiating ATGís for the A and B forms of the PR.
The PR mutation was established in both a C57BL6/129SvEv hybrid and 129SvEv inbreed genetic background.
Future Directions
The expression of potential PR target genes are now being examined in this mutant.
Finally, future investigations will explore whether this PR mutation alters the
susceptibility of this mouse strain to mammary gland carcinogenesis as compared to wild
types.
PR, gene targeting, lobuloalveolar development
John P. Lydon
Department of Cell Biology
Baylor College of Medicine
#1 Baylor Plaza
Houston, TX, 77030
Phone : 713-798-6229
Fax : 713-790-1275
E-mail: (jlydon@bcm.tmc.edu)
contributed: December, 1995
last update: December 1998