title: Hypothalamic but not pituitary or ovarian defects underlie the reproductive abnormalities in Axl/Tyro3 null mice.
abstract: AXL and TYRO3, members of the TYRO3, AXL and MER (TAM) family of tyrosine kinase receptors, modulate GnRH neuronal cell migration, survival and gene expression. Axl/Tyro3 null mice exhibit a selective loss of GnRH neurons, delayed sexual maturation and irregular estrous cycles. Here we determined whether the defects were due to direct ovarian defects, altered pituitary sensitivity to GnRH and/or an impaired LH surge mechanism. Ovarian histology and markers of folliculogenesis and atresia as well as corpora luteal development and ovarian response to superovulation were not impaired. Axl/Tryo3 null mice exhibited a robust LH response to exogenous GnRH, suggesting no altered pituitary sensitivity. Ovariectomized Axl/Tyro3 null mice, however, demonstrated an impaired ability to mount a steroid-induced LH surge. Loss of GnRH neurons in Axl/Tyro3 null mice impairs the sex hormone-induced gonadotropin surge resulting in estrous cycle abnormalities confirming that TAM family members contribute to normal female reproductive function.
authors.affiliation: Department of Medicine, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Pierce
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Brian
authors.initials: B
authors.lastname: Bliesner
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Liu
authors.forename: JoAnne
authors.initials: J
authors.lastname: Richards
authors.forename: Stuart
authors.initials: S
authors.lastname: Tobet
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Wierman
mesh_terms: D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D030762:Estrous Cycle / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology*; D013480:Superovulation; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D002786:Cholesterol Side-Chain Cleavage Enzyme; D006063:Chorionic Gonadotropin; D005640:Follicle Stimulating Hormone; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse