Alterted SLIT2/ROBO1 Signalling Is Linked to Impaired Placentation of Missed and Threatened Miscarriage in Early Pregnancy

Histopathology. 2017 Oct;71(4):543-552. doi: 10.1111/his.13250. Epub 2017 Jul 11.


Aims: Two-thirds of early pregnancy failures present with reduced trophoblast invasion, and SLIT2/ROBO1 signalling is considered to play an important role in trophoblast function during pregnancy. We investigated SLIT2/ROBO1 signalling associated with missed and threatened miscarriage during early gestation.

Methods and results: Human placenta samples were collected from women with missed miscarriage (n = 25), threatened miscarriage (n = 22) and termination of pregnancy controls (n = 32). Corresponding decreases in beta human chorionic gonadotrophin (β-hCG) levels and shallow trophoblast invasion were observed in patients with missed and threatened miscarriage, immunohistological staining revealed abnormal Slit2 and Robo1, as well as E-cadherin and activating protein-2 alpha (AP-2α) expression in villi and extravillous trophoblasts, and the expression of these proteins were confirmed in villi and decidua of miscarriage material by Western blotting. Using HTR8/SVneo cells, blocking SLIT2/ROBO1 signalling promoted cell migration, proliferation and suppressed differentiation. Moreover, blocking SLIT2/ROBO1 signalling in HTR8/SVneo cells altered trophoblast differentiation-related and angiogenesis-related gene mRNA expression, which also occurred in the tissues of missed and threatened miscarriage.

Conclusions: SLIT2/ROBO1 signalling may regulate trophoblast differentiation and invasion causing restricting β-hCG production, shallow trophoblast invasion and inhibiting placental angiogenesis in missed and threatened miscarriage during the first trimester.

Keywords: differentiation; invasion; miscarriage; trophoblast.

MeSH terms

  • Abortion, Spontaneous / etiology*
  • Abortion, Spontaneous / metabolism
  • Abortion, Spontaneous / pathology
  • Abortion, Threatened / etiology*
  • Abortion, Threatened / metabolism
  • Abortion, Threatened / pathology
  • Adult
  • Antigens, CD
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Movement
  • Chorionic Gonadotropin, beta Subunit, Human / metabolism
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Placenta / metabolism
  • Placenta / pathology
  • Placentation
  • Pregnancy
  • Pregnancy Trimester, First
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction*
  • Trophoblasts / metabolism
  • Trophoblasts / pathology
  • Young Adult


  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Chorionic Gonadotropin, beta Subunit, Human
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • roundabout protein
  • Slit homolog 2 protein