Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts.
Trophoblast invasion of the uterine extracellular matrix, a critical process of human implantation and essential for fetal development, is a striking example of controlled invasiveness. To identify molecules that regulate trophoblast invasion, mRNA signatures of trophoblast cells isolated from first trimester (high invasiveness) and term placentae (no/low invasiveness) were compared using U95A GeneChip microarrays yielding 220 invasion/migration-related genes. In this 'invasion cluster', KiSS-1 and its G-protein-coupled receptor KiSS-1R were expressed at higher levels in first trimester trophoblasts than at term of gestation. Receptor and ligand mRNA and protein were localized to the trophoblast compartment. In contrast to KiSS-1, which is only expressed in the villous trophoblast, KiSS-1R was also found in the extravillous trophoblast, suggesting endocrine/paracrine activation mechanisms. The primary translation product of KiSS-1 is a 145 amino acid polypeptide (Kp-145), but shorter kisspeptins (Kp) with 10, 13, 14 or 54 amino acid residues may be produced. We identified Kp-10, a dekapeptide derived from the primary translation product, in conditioned medium of first trimester human trophoblast. Kp-10, but not other kisspeptins, increased intracellular Ca(2+) levels in isolated first trimester trophoblasts. Kp-10 inhibited trophoblast migration in an explant as well as transwell assay without affecting proliferation. Suppressed motility was paralleled with suppressed gelatinolytic activity of isolated trophoblasts. These results identified Kp-10 as a novel paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself.
Bilban
Martin
M
Department of Cell Biology, The Scripps Research Institute, North Torrey Pines Road, La Jolla, CA 92037, USA.
Ghaffari-Tabrizi
Nassim
N
Hintermann
Edith
E
Bauer
Sandra
S
Molzer
Sylvia
S
Zoratti
Cristina
C
Malli
Roland
R
Sharabi
Andrew
A
Hiden
Ursula
U
Graier
Wolfgang
W
Knöfler
Martin
M
Andreae
Fritz
F
Wagner
Oswald
O
Quaranta
Vito
V
Desoye
Gernot
G
D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000737:chemistry; D016895:Culture Media, Serum-Free; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D059648:Kisspeptins; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides; D009924:Organ Culture Techniques; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D010920:Placenta / Q000737:chemistry; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011506:Proteins / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D014327:Trophoblasts / Q000737:chemistry / Q000166:cytology* / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; C106628:KISS1 protein, human; D059648:Kisspeptins; D009842:Oligopeptides; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D002118:Calcium