Regulation and function of LEFTY-A/EBAF in the human endometrium. mRNA expression during the menstrual cycle, control by progesterone, and effect on matrix metalloprotineases.
The human endometrium is a unique tissue that is periodically shed during menstruation. Although overall triggered by ovarian steroids withdrawal, menstrual induction of matrix metalloproteinases (MMPs) and resulting tissue breakdown are focal responses, pointing to additional local modulators. LEFTY-A, a novel member of the transforming growth factor-beta family identified originally as an endometrial bleeding-associated factor (EBAF), is a candidate for this local control. We measured LEFTY-A and beta-ACTIN mRNA concentration during the menstrual cycle in vivo and found that their ratio was dramatically ( approximately 100-fold) increased at the perimenstrual phase. A similar increase was seen when proliferative explants were cultured for 24 h in the absence of ovarian steroids; this was followed by spontaneous production of proMMP-1, -3, and -9. Both responses were inhibited by progesterone. Moreover, addition of recombinant LEFTY-A to proliferative explants was sufficient to stimulate the expression of proMMP-3 and -7; this response was also blocked by ovarian steroids. Collectively, these data indicate that LEFTY-A may provide a crucial signal for endometrial breakdown and bleeding by triggering expression of several MMPs. Progesterone appears to exert a dual block, upstream by inhibiting LEFTY-A expression and downstream by suppressing its stimulatory effect on MMPs.
Cornet
Patricia B
PB
Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Avenue Hippocrate, 75, B-1200 Bruxelles, Belgium.
Picquet
Christine
C
Lemoine
Pascale
P
Osteen
Kevin G
KG
Bruner-Tran
Kaylon L
KL
Tabibzadeh
Siamak
S
Courtoy
Pierre J
PJ
Eeckhout
Yves
Y
Marbaix
Etienne
E
Henriet
Patrick
P
D000199:Actins / Q000378:metabolism; D001483:Base Sequence; D017931:DNA Primers; D004717:Endometrium / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D055458:Left-Right Determination Factors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008597:Menstrual Cycle / Q000502:physiology*; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; C526161:LEFTY1 protein, human; D055458:Left-Right Determination Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D011374:Progesterone; D020782:Matrix Metalloproteinases