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Endocrinology. 2014 Sep;155(9):3661-73. doi: 10.1210/en.2014-1341. Epub 2014 Jun 27.

ROS1 signaling regulates epithelial differentiation in the epididymis.

Author information

1
Molecular Oncology Research Institute (H.J.J., S.W., D.P., A.C), Tufts Medical Center, Boston, Massachusetts 02111; Center for Cancer Research (K.L., A.C.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; Program in Membrane Biology and Division of Nephrology and Center for Systems Biology (J.R., T.B.S., S.B.) and Molecular Pathology Unit (L.B.W., K.M.H.), Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Pathology (R.T.B), Harvard Medical School, Boston, Massachusetts 02115; and Department of Neurosurgery and Program in Genetics (A.C), Tufts University School of Medicine, Boston, Massachusetts 02111.

Abstract

The initial segment (IS) of the epididymis plays an essential role in male fertility. The IS epithelium is undifferentiated and nonfunctional at birth. Prior to puberty, the epithelium undergoes differentiation that leads to the formation of a fully functional organ. However, the mechanistic details of this program are not well understood. To explore this further, we used genetic engineering to create a kinase dead allele of the ROS1 receptor tyrosine kinase in mice and studied the effects of ROS1 tyrosine kinase activity on the differentiation of the IS epithelium. We show that the expression and activation of ROS1 coincides with the onset of differentiation and is exclusively located in the IS of the maturing and adult mouse epididymides. Here we demonstrate that the differentiation of the IS is dependent on the kinase activity of ROS1 and its downstream effector MEK1/2-ERK1/2 signaling axis. Using genetic engineering, we show that germ line ablation of ROS1 kinase activity leads to a failure of the IS epithelium to differentiate, and as a consequence sperm maturation and infertility were dramatically perturbed. Pharmacological inhibition of ROS1 kinase activity in the developing epididymis, however, only delayed differentiation transiently and did not result in infertility. Our results demonstrate that ROS1 kinase activity and the ensuing MEK1/2-ERK1/2 signaling are necessary for the postnatal development of the IS epithelium and that a sustained ablation of ROS1 kinase activity within the critical window of terminal differentiation abrogate the function of the epididymis and leads to sterility.

PMID:
24971615
PMCID:
PMC4138574
DOI:
10.1210/en.2014-1341
[Indexed for MEDLINE]
Free PMC Article

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