Placenta-specific Slc38a2/SNAT2 knockdown causes fetal growth restriction in mice

Clin Sci (Lond). 2021 Sep 17;135(17):2049-2066. doi: 10.1042/CS20210575.


Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR.

Keywords: MeAIB; amino acid transport system A; fetal growth restriction; lentivirus; maternal-fetal exchange; syncytiotrophoblast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System A / deficiency*
  • Amino Acid Transport System A / genetics
  • Animals
  • Case-Control Studies
  • Female
  • Fetal Development*
  • Fetal Growth Retardation / genetics
  • Fetal Growth Retardation / metabolism*
  • Fetal Growth Retardation / physiopathology
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Placenta / metabolism*
  • Placenta / physiopathology
  • Placentation*
  • Pregnancy
  • Prospective Studies
  • RNA Interference


  • Amino Acid Transport System A
  • SLC38A2 protein, human
  • Slc38a2 protein, mouse