Socs2 and elf5 mediate prolactin-induced mammary gland development.
The proliferative phase of mammary alveolar morphogenesis is initiated during early pregnancy by rising levels of serum prolactin and progesterone, establishing a program of gene expression that is ultimately responsible for the development of the lobuloalveoli and the onset of lactation. To explore this largely unknown genetic program, we constructed transcript profiles derived from transplanted mammary glands formed by recombination of prolactin receptor (Prlr) knockout or wild-type mammary epithelium with wild-type mammary stroma. Comparison with profiles derived from prolactin-treated Scp2 mammary epithelial cells produced a small set of commonly prolactin-regulated genes that included the negative regulator of cytokine signaling, Socs2 (suppressor of cytokine signaling 2), and the ets transcription factor, E74-like factor 5 (Elf5). Homozygous null mutation of Socs2 rescued the failure of lactation and reduction of mammary signal transducer and activator of transcription 5 phosphorylation that characterizes Prlr heterozygous mice, demonstrating that mammary Socs2 is a key regulator of the prolactin-signaling pathway. Reexpression of Elf5 in Prlr nullizygous mammary epithelium restored lobuloalveolar development and milk production, demonstrating that Elf5 is a transcription factor capable of substituting for prolactin signaling. Thus, Socs2 and Elf5 are key members of the set of prolactin-regulated genes that mediate prolactin-driven mammary development.
Harris
Jessica
J
Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
Stanford
Prudence M
PM
Sutherland
Kate
K
Oakes
Samantha R
SR
Naylor
Matthew J
MJ
Robertson
Fiona G
FG
Blazek
Katrina D
KD
Kazlauskas
Michael
M
Hilton
Heidi N
HN
Wittlin
Sergio
S
Alexander
Warren S
WS
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
Ormandy
Christopher J
CJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C500759:Elf5 protein, mouse; D012333:RNA, Messenger; D011981:Receptors, Prolactin; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D011388:Prolactin