Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia.
The essential role of connexin43 (Cx43) during oogenesis has been demonstrated by the severe germ cell deficiency and arrested folliculogenesis observed in Cx43 knockout mice. Recently, another mutant mouse strain became available (Gja1(Jrt)/+) that carries the dominant loss-of-function Cx43 mutation, Cx43(G60S). Gja1(Jrt)/+ mice display features of the human disease oculodentodigital dysplasia (ODDD), which is caused by mutations in the GJA1 gene. We used this new mutant strain to study how a disease-linked Cx43 mutant affects oogenesis. We found that female mutant mice are subfertile with significantly reduced mating success and small litters. The phosphorylated species of the Cx43 protein are reduced in the mutant ovaries in association with impaired trafficking and assembly of gap junctions in the membranes of granulosa cells, confirming that the mutant protein acts dominantly on its wild-type counterpart. Correspondingly, although starting with a normal abundance of germ cells, ovaries of the mutant mice contain significantly fewer pre-ovulatory follicles and do not respond to superovulation by gonadotropins, which is at least partially the result of reduced proliferation and increased apoptosis of granulosa cells. We conclude that the Gja1(Jrt) mutation has a dominant negative effect on Cx43 function in the ovary, rendering the females subfertile. Given these findings, closer examination of reproductive function in ODDD human females is warranted.
Tong
Dan
D
Department of Physiology and Pharmacology, The University of Western Ontario, London, Canada.
Colley
Deanne
D
Thoo
Renee
R
Li
Tony Y
TY
Plante
Isabelle
I
Laird
Dale W
DW
Bai
Donglin
D
Kidder
Gerald M
GM
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D006107:Granulosa Cells / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009866:Oogenesis / Q000235:genetics*; D014071:Tooth Abnormalities / Q000235:genetics*
D018031:Connexin 43; C543076:GJA1 protein, mouse