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A more recent version of this article appeared on October 1, 2002
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Submitted on March 13, 2002
Revised on June 25, 2002
Accepted on July 10, 2002
1 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA; and Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
2 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA
* Corresponding author. E-mail address: trm4{at}med.unc.edu.
Sorting nexins 1 (Snx1) and 2 (Snx2) are homologs of the yeast gene VPS5 that is required for proper endosome-to-Golgi trafficking. The prevailing thought is that Vps5p is a component of a retrograde trafficking complex called the retromer. Genetic and biochemical evidence suggest mammals may have similar complexes, but their biological role is unknown. Furthermore, if SNX1 and SNX2 belong to such complexes, it is not known whether they act together or separately. Here we show that mice lacking SNX1 or SNX2 are viable and fertile, while embryos deficient in both proteins arrest at midgestation. These results demonstrate that SNX1 and SNX2 have a highly redundant and necessary function in the mouse. The phenotype of Snx1-/-;Snx2-/- embryos is very similar to embryos lacking another retromer homolog, Hß58. This finding suggests that SNX1/SNX2 and Hß58 function in the same genetic pathway, providing additional evidence for the existence of mammalian complexes that are structurally similar to the yeast retromer. Furthermore, the viability of Snx1-/- and Snx2-/- mice demonstrates that it is not necessary for SNX1 and SNX2 to act together. Electron microscopy indicates morphological alterations of apical intracellular compartments in the Snx1-/-;Snx2-/- yolk-sac visceral endoderm, suggesting SNX1 and SNX2 may be required for proper cellular trafficking. However, tetraploid aggregation experiments suggest that yolk sac defects cannot fully account for Snx1-/-;Snx2-/- embryonic lethality. Furthermore, endocytosis of transferrin and LDL is unaffected in mutant embryonic fibroblasts indicating that SNX1 and SNX2 are not essential for endocytosis in all cells. Although the two proteins demonstrate functional redundancy, Snx1+/-;Snx2-/- mice display abnormalities not observed in Snx1-/-;Snx2+/- mice, revealing that SNX1 and SNX2, or their genetic regulation, are not equivalent. Significantly, these studies represent the first mutations in the mammalian sorting nexin gene family and indicate that sorting nexins perform essential functions in mammals.
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