Differential functions of the Apoer2 intracellular domain in selenium uptake and cell signaling

Biol Chem. 2009 Jan;390(1):67-73. doi: 10.1515/BC.2009.011.


Apolipoprotein E receptor 2 (Apoer2) is a multifunctional transport and signaling receptor that regulates the uptake of selenium into the mouse brain and testis through endocytosis of selenoprotein P (Sepp1). Mice deficient in Apoer2 or Sepp1 are infertile, with kinked and hypomotile spermatozoa. They also develop severe neurological defects on a low selenium diet, due to a profound impairment of selenium uptake. Little is known about the function of Apoer2 in the testis beyond its role as a Sepp1 receptor. By contrast, in the brain, Apoer2 is an essential component of the Reelin signaling pathway, which is required for proper neuronal organization and synapse function. Using knock-in mice, we have functionally dissociated the signaling motifs in the Apoer2 cytoplasmic domain from Sepp1 uptake. Selenium concentration of brain and testis was normal in the knock-in mutants, in contrast to Apoer2 knock-outs. Thus, the neurological defects in the signaling impaired knock-in mice are not caused by a selenium uptake defect, but instead are a direct consequence of a disruption of the Reelin signal. Reduced sperm motility was observed in some of the knock-in mice, indicating a novel signaling role for Apoer2 in sperm development and function that is independent of selenium uptake.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Transport
  • Brain / metabolism
  • Cytoplasm / metabolism
  • Endocytosis*
  • Gene Knock-In Techniques
  • Intracellular Space / metabolism*
  • LDL-Receptor Related Proteins
  • Male
  • Mice
  • Mutation
  • Protein Structure, Tertiary
  • Receptors, Lipoprotein / chemistry*
  • Receptors, Lipoprotein / genetics
  • Receptors, Lipoprotein / metabolism*
  • Selenium / metabolism*
  • Signal Transduction*
  • Sperm Motility
  • Spermatozoa / classification
  • Spermatozoa / cytology
  • Spermatozoa / metabolism
  • Testis / metabolism


  • LDL-Receptor Related Proteins
  • Receptors, Lipoprotein
  • low density lipoprotein receptor-related protein 8
  • Selenium