title: Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism.
abstract: Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Witek
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Abeer
authors.initials: A
authors.lastname: El Wakil
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Nord
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ahlgren
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Institution for Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Vernersson-Lindahl
authors.affiliation: Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
authors.affiliation: Institution for Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Alexeyev
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Hallberg
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D055786:Gene Knockout Techniques; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000378:metabolism; D007006:Hypogonadism / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013076:Sperm Count; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism
chemical_list: D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases