title: Olfactomedin 1 Deficiency Leads to Defective Olfaction and Impaired Female Fertility.
abstract: Olfactomedin 1 (OLFM1) is a glycoprotein highly expressed in the brain. Olfm1(-/-) female mice were previously reported to have reduced fertility. Previous microarray analysis revealed Olfm1 among the most highly upregulated genes in the uterine luminal epithelium upon embryo implantation, which was confirmed by in situ hybridization. We hypothesized that Olfm1 deficiency led to defective embryo implantation and thus impaired fertility. Indeed, Olfm1(-/-) females had defective embryo implantation. However, Olfm1(-/-) females rarely mated and those that mated rarely became pregnant. Ovarian histology indicated the absence of corpora lutea in Olfm1(-/-) females, indicating defective ovulation. Superovulation using equine chorionic gonadotropin-human chorionic gonadotropin rescued mating, ovulation, and pregnancy, and equine chorionic gonadotropin alone rescued ovulation in Olfm1(-/-) females. Olfm1(-/-) females had a 13% reduction of hypothalamic GnRH neurons but comparable basal serum LH levels and GnRH-induced LH levels compared with wild-type controls. These results indicated no obvious local defects in the female reproductive system and a functional hypothalamic-pituitary-gonadal axis. Olfm1(-/-) females were unresponsive to the effects of male bedding stimulation on pubertal development and estrous cycle. There were 41% fewer cFos-positive cells in the mitral cell layer of accessory olfactory bulb upon male urine stimulation for 90 minutes. OLFM1 was expressed in the main and accessory olfactory systems including main olfactory epithelium, vomeronasal organ, main olfactory bulb, and accessory olfactory bulb, with the highest expression detected in the axon bundles of olfactory sensory neurons. These data demonstrate that defective fertility in Olfm1(-/-) females is most likely a secondary effect of defective olfaction.
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Honglu
authors.initials: H
authors.lastname: Diao
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Shuo
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: El Zowalaty
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Dudley
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Department of Physiology and Pharmacology (R.L., H.D., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), College of Veterinary Medicine, and Interdisciplinary Toxicology Program (R.L., F.Z., S.X., A.E.E.Z., E.A.D., X.Y.), University of Georgia, Athens, Georgia 30602; and Laboratory of Neurosciences (M.P.M.), National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Ye
mesh_terms: D000818:Animals; D010064:Embryo Implantation; D016326:Extracellular Matrix Proteins / Q000172:deficiency*; D005260:Female; D005298:Fertility; D006023:Glycoproteins / Q000172:deficiency*; D007031:Hypothalamus / Q000502:physiology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D057507:Mice, 129 Strain; D009812:Odorants; D009830:Olfactory Bulb / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000378:metabolism; D010060:Ovulation; D011897:Random Allocation; D012726:Sexual Behavior, Animal / Q000502:physiology; D012903:Smell; D013480:Superovulation; D014599:Uterus / Q000378:metabolism; D019147:Vomeronasal Organ / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C081451:olfactomedin; D007986:Luteinizing Hormone