Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism

PLoS One. 2015 May 8;10(5):e0123542. doi: 10.1371/journal.pone.0123542. eCollection 2015.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Gene Knockout Techniques
  • Gonadotropin-Releasing Hormone / blood
  • Gonadotropin-Releasing Hormone / metabolism
  • Hypogonadism / blood
  • Hypogonadism / genetics
  • Hypogonadism / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Sperm Count
  • Spermatozoa / cytology
  • Spermatozoa / metabolism
  • Testosterone / blood
  • Testosterone / metabolism


  • Gonadotropin-Releasing Hormone
  • Testosterone
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases

Grants and funding

Work in the author’s laboratories has been supported by grants from the Swedish Cancer Society (BH 12-0722, RHP 12-0796), the Children’s Cancer Foundation (BH 11/020, RHP 13/0049), the Swedish Research Council (RHP 621-2011-5181, BH 521-2012-2831), Lions Cancer Society, Umeå (BH and RHP LP 12-1946), the JC Kempe Foundation (BH and RHP) and FP-People-2011-IAPP (BH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.