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Vol. 13, Issue 10, 3588-3600, October 2002
*Department of Genetics, University of North Carolina, Chapel Hill,
North Carolina 27599; and Sorting nexins 1 (Snx1) and 2 (Snx2)
are homologues 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. Herein, we show that mice lacking SNX1 or
SNX2 are viable and fertile, whereas 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 that of embryos lacking another retromer homologue, HDepartment of Genetics,
Case Western Reserve University School of Medicine, Cleveland, Ohio
44106
58. This finding suggests that SNX1/SNX2 and H58 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 low-density lipoprotein is
unaffected in mutant primary 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.
Corresponding author. E-mail address:
trm4{at}med.unc.edu.
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