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Gene Review

INSL4  -  insulin-like 4 (placenta)

Homo sapiens

Synonyms: EPIL, Early placenta insulin-like peptide, Insulin-like peptide 4, PLACENTIN, Placentin
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Disease relevance of INSL4

  • We identified an unexpected human endogenous retrovirus (HERV) element inserted into the human INSL4 promoter with a sequence similar to that of env gene, flanked by two long terminal repeats(LTRs) [1].
  • Immunohistochemistry on tissue microarrays revealed a heterogeneous expression of EPIL in breast cancer tissue and no expression in the surrounding stroma cells [2].

High impact information on INSL4

  • By differential-display PCR a subclone of the SKBR3 cell line with high in vitro transendothelial invasiveness was identified to express increased levels of the INSL-4 gene [2].
  • This new member of the insulin-like growth factor family encodes for a peptide, designated early placenta insulin-like (EPIL), being expressed in the so-called "invasive" phase of the placental development [2].
  • Moreover, in cytotrophoblast primary culture, production of chorionic gonadotropin, a marker of trophoblast differentiation, was increased upon treatment with placentin-conditioned media, while unaffected by insulin [3].
  • While these effects closely mimicked those of insulin, they were not mediated by the insulin receptor as shown by the lack of tyrosine phosphorylation of this receptor upon placentin treatment [3].
  • Conditioned media produced by recombinant expression of placentin cDNA in the placental 3AsubE cell line were assayed for biological activity and found to stimulate tyrosine phosphorylation and DNA synthesis [3].

Biological context of INSL4

  • Transient transfection experiments showed that the placenta-specific expression of INSL4 is mediated by the 3' LTR of the HERV element, and that the latter may have a major role in INSL4 up-regulation during human cytotrophoblast differentiation into syncytiotrophoblast [1].
  • Here we have mapped INSL4 within the framework of a partial YAC contig covering the distal part of 9p to find out whether this gene lies within the critical region defined for the monosomy 9p syndrome [4].
  • We used primary amniotic epithelial cells for flow cytometry to show that INSL4 caused apoptosis, which was dose-related and significant (P < 0.05) at 50 ng/ml [5].
  • Expression of the INSL4 gene was doubled in the placenta of the growth-restricted twin compared to the normally grown sibling, suggesting that it may be linked to a higher level of apoptosis and loss of cell viability and, therefore, that it may contribute to fetal growth restriction [5].
  • The addition of INSL4 (3-30 ng/ml) also caused a loss of cell viability, although it had no effect on the numbers of cells at different phases of the cell cycle [5].

Anatomical context of INSL4

  • Expression of INSL4, of unknown function, has been recently detected in the perichondrium and ligaments of the human embryo [4].
  • Although an abundance of locally acting growth factors are produced within the uterus during pregnancy, we hypothesized that INSL4 plays an important role in fetal and placental growth [5].
  • In fetal tissues, INSL4 mRNA was identified in the perichondrium of all four limbs, vertebrae, and ribs [6].
  • The insect developmental factor bombyxin, the relaxin-like factor from Leydig cells, and the insulin-like factor 4 (INSL4) all are made of two disulfide-linked chains and have one disulfide bond within the A-chain [7].
  • Early placental insulin-like protein (INSL4 or EPIL) in placental and fetal membrane growth [5].

Associations of INSL4 with chemical compounds

  • Tris/Tricine/SDS-polyacrylamide gel electrophoresis and immunoblot analyses of histidine-tagged recombinant placentin indicate that it is composed of two peptide chains of apparent molecular masses of 4 and 13 kDa [3].

Other interactions of INSL4

  • The INSL4 gene maps close to WI-5527 at 9p24.1-->p23.3 clustered with two relaxin genes and outside the critical region for the monosomy 9p syndrome [4].
  • These transcriptional expression profiles are in favor of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive and migratory properties of trophoblast cells [8].

Analytical, diagnostic and therapeutic context of INSL4

  • The insulin like growth factor 4 (INSL4) gene belongs to the insulin gene superfamily and has been mapped by fluorescent in situ hybridization to 9p24 [4].
  • By in situ hybridization, the INSL4 gene was assigned to band p24 of the short arm of chromosome 9 [9].
  • Using RT-PCR, we previously found abundant INSL4 mRNA in the human placenta [6].
  • Recent observations based on immunohistochemistry and RT-PCR demonstrate that early placenta insulin-like peptide (EPIL), encoded by the INSL4 gene, is present in the placenta during gestation [10].
  • The recent development of a specific immunoassay based on monoclonal antibodies directed to chain C and chain A of early placenta insulin-like peptide (EPIL) encoded by the INSL4 gene, has made it possible to demonstrate pro-EPIL peptide expression during normal pregnancy [11].


  1. Placenta-specific INSL4 expression is mediated by a human endogenous retrovirus element. Bièche, I., Laurent, A., Laurendeau, I., Duret, L., Giovangrandi, Y., Frendo, J.L., Olivi, M., Fausser, J.L., Evain-Brion, D., Vidaud, M. Biol. Reprod. (2003) [Pubmed]
  2. Early placenta insulin-like growth factor (pro-EPIL) is overexpressed and secreted by c-erbB-2-positive cells with high invasion potential. Brandt, B., Roetger, A., Bidart, J.M., Packeisen, J., Schier, K., Mikesch, J.H., Kemming, D., Boecker, W., Yu, D., Buerger, H. Cancer Res. (2002) [Pubmed]
  3. Molecular characterization and in vitro biological activity of placentin, a new member of the insulin gene family. Koman, A., Cazaubon, S., Couraud, P.O., Ullrich, A., Strosberg, A.D. J. Biol. Chem. (1996) [Pubmed]
  4. The INSL4 gene maps close to WI-5527 at 9p24.1-->p23.3 clustered with two relaxin genes and outside the critical region for the monosomy 9p syndrome. Veitia, R., Laurent, A., Quintana-Murci, L., Ottolenghi, C., Fellous, M., Vidaud, M., McElreavey, K. Cytogenet. Cell Genet. (1998) [Pubmed]
  5. Early placental insulin-like protein (INSL4 or EPIL) in placental and fetal membrane growth. Millar, L., Streiner, N., Webster, L., Yamamoto, S., Okabe, R., Kawamata, T., Shimoda, J., Büllesbach, E., Schwabe, C., Bryant-Greenwood, G. Biol. Reprod. (2005) [Pubmed]
  6. Insulin-like 4 (INSL4) gene expression in human embryonic and trophoblastic tissues. Laurent, A., Rouillac, C., Delezoide, A.L., Giovangrandi, Y., Vekemans, M., Bellet, D., Abitbol, M., Vidaud, M. Mol. Reprod. Dev. (1998) [Pubmed]
  7. Chemical synthesis of a Zwitterhormon, insulaxin, and of a relaxin-like bombyxin derivative. Büllesbach, E.E., Steinetz, B.G., Schwabe, C. Biochemistry (1996) [Pubmed]
  8. Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells. Janneau, J.L., Maldonado-Estrada, J., Tachdjian, G., Miran, I., Motté, N., Saulnier, P., Sabourin, J.C., Coté, J.F., Simon, B., Frydman, R., Chaouat, G., Bellet, D. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  9. Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta. Chassin, D., Laurent, A., Janneau, J.L., Berger, R., Bellet, D. Genomics (1995) [Pubmed]
  10. Pro-EPIL forms are present in amniotic fluid and maternal serum during normal pregnancy. Mock, P., Frydman, R., Bellet, D., Diawara, D.A., Lavaissiere, L., Troalen, F., Bidart, J.M. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  11. Expression of pro-EPIL peptides encoded by the insulin-like 4 (INSL4) gene in chromosomally abnormal pregnancies. Mock, P., Frydman, R., Bellet, D., Chassin, D., Bischof, P., Campana, A., Bidart, J.M. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
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