The acrosomal protein Dickkopf-like 1 (DKKL1) facilitates sperm penetration of the zona pellucida.
OBJECTIVE
To determine the role of Dkkl1 in mouse development, viability, and fertility.


METHODS
Prospective experimental study.


METHODS
Government research institution.


METHODS
Mice of C57BL/6, B6D2F1/J, and 129X1/SvJ strains, as well as transgenic mice of mixed C57BL/6 and 129X1/SvJ strains were used for the studies.


METHODS
Expression of the Dkkl1 gene was characterized during early mouse development, and the effects of Dkkl1 ablation on reproduction and fertility were characterized in vitro and in vivo.


METHODS
Dkkl1 RNA expression was determined by Northern blotting hybridization as well as quantitative reverse transcriptase-polymerase chain reaction assays. In vitro fertilization assays were used to assess fertility of sperm from male mice lacking functional Dkkl1.


RESULTS
Dkkl1 is a gene unique to mammals that is expressed primarily in developing spermatocytes and its product localized in the acrosome of mature sperm. Here we show that Dkkl1 also is expressed in the trophectoderm/placental lineage. Surprisingly, embryos lacking DKKL1 protein developed into viable, fertile adults. Nevertheless, the ability of sperm that lacked DKKL1 protein to fertilize wild-type eggs was severely compromised in vitro. Because this defect could be overcome either by removal of the zona pellucida or by the presence of wild-type sperm, Dkkl1, either directly or indirectly, facilitates the ability of sperm to penetrate the zona pellucida. Penetration of the zona pellucida by Dkkl1(-) sperm was delayed in vivo as well as in vitro, but the delay in vivo was compensated by other factors during preimplantation development. Accordingly, Dkkl1-/- males offer an in vitro fertilization model for identifying factors that may contribute to infertility.


CONCLUSIONS
DKKL1 is a mammalian-specific, acrosomal protein that strongly affects in vitro fertilization, although the effect is attenuated in vivo.
Kohn
Matthew J
MJ
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2753, USA.
Sztein
Jorge
J
Yagi
Rieko
R
DePamphilis
Melvin L
ML
Kaneko
Kotaro J
KJ
D000177:Acrosome / Q000378:metabolism*; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D015152:Blotting, Northern; D019070:Cell Lineage; D005260:Female; D005298:Fertility; D005307:Fertilization in Vitro; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013084:Sperm-Ovum Interactions; D015044:Zona Pellucida / Q000378:metabolism*
D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C414705:soggy protein, mouse