Inactivation of Cops5 in Smooth Muscle Cells Causes Abnormal Reproductive Hormone Homeostasis and Development in Mice

Abstract

COP9 constitutive photomorphogenic homolog subunit 5 (COPS5), also known as Jab1 or CSN5, has been implicated in a wide variety of cellular and developmental processes. By analyzing male germ cell-specific COPS5-deficient mice, we have demonstrated previously that COPS5 is essential to maintain male germ survival and acrosome biogenesis. To further determine the role of Cops5 in peritubular myoid cells, a smooth muscle lineage surrounding seminiferous tubules, we herein derived mice conditionally deficient for the Cops5 gene in smooth muscle cells using transgenic Myh11-Cre mice. Although these conditional Cops5-deficient mice were born at the expected Mendelian ratio and appeared to be normal within the first week after birth, the homozygous mice started to show growth retardation after 1 week. These mice also exhibited a variety of developmental and reproductive disorders, including failure of development of reproductive organs in both males and females, spermatogenesis defects, and impaired skeletal development and immune functions. Furthermore, conditional Cops5-deficient mice revealed dramatic impairment of the endocrine system associated with testicular functions, including a marked reduction in serum levels of gonadotropins (follicle-stimulating hormone, luteinizing hormone), testosterone, insulin-like growth factor 1, and glucose, but not vasopressin. All homozygous mice died before age 67 days in the study. Collectively, our results provide novel evidence that Cops5 in smooth muscle lineage plays an essential role in postnatal development and reproductive functions.

Keywords: COPS5; endocrine system; hormone homeostasis; immune functions; reproduction; skeletal development; smooth muscle cells.