Male infertility and DNA damage in Doppel knockout and prion protein/Doppel double-knockout mice.
The prion protein (PrP) and Doppel (Dpl) have many structural and biochemical properties in common, leading to the suggestion that the lack of an obvious phenotype in PrP-deficient mice maybe because of compensation by Dpl. To test this hypothesis and also investigate the function of Dpl we have generated Prnd(-/-) and Prnp(-/-)/Prnd(-/-) mouse lines. Both develop normally and display an identical male sterility phenotype that differs from that reported for another Prnd(-/-) mouse line. Sperm from both our mutant lines were present at normal concentrations, had normal motility, and no morphological abnormalities. Despite only rarely fertilizing oocytes in vivo, because of an inability to perform the acrosome reaction, mutant sperm were capable of fertilization in vitro, albeit at reduced rates compared to wild type. Elevated levels of oxidative DNA damage were found in both types of mutant sperm and resulting embryos failed at an early stage. Therefore we found no evidence that Dpl compensates for the loss of PrP function in mutant mouse lines, but it does have an important anti-oxidant function necessary for sperm integrity and male fertility.
Paisley
Derek
D
Molecular Medicine Centre, University of Edinburgh, Edinburgh, Scotland.
Banks
Stephen
S
Selfridge
Jim
J
McLennan
Neil F
NF
Ritchie
Ann-Marie
AM
McEwan
Carolanne
C
Irvine
D Stewart
DS
Saunders
Philippa T K
PT
Manson
Jean C
JC
Melton
David W
DW
D020101:Acrosome Reaction; D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000473:pathology / Q000648:ultrastructure; D004249:DNA Damage / Q000235:genetics*; D017931:DNA Primers; D004822:Epididymis; D005307:Fertilization in Vitro; D058851:GPI-Linked Proteins; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011328:Prions / Q000235:genetics* / Q000502:physiology; D013081:Sperm Motility; D013094:Spermatozoa / Q000166:cytology / Q000473:pathology / Q000502:physiology
D002843:Chromatin; D017931:DNA Primers; D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse