Differential functions of the Apoer2 intracellular domain in selenium uptake and cell signaling.
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.
Masiulis
Irene
I
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Quill
Timothy A
TA
Burk
Raymond F
RF
Herz
Joachim
J
D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis; D055879:Gene Knock-In Techniques; D042541:Intracellular Space / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D008297:Male; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D012643:Selenium / Q000378:metabolism*; D015398:Signal Transduction; D013081:Sperm Motility; D013094:Spermatozoa / Q000145:classification / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012643:Selenium