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research-article |
Division of Developmental Genetics,3 Institute of Molecular Embryology and Genetics, and Division of Reproductive Engineering,4 Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
Department of Cell Pathology,5 Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
ABSTRACT
The roles of the leucine-rich repeat domain containing G protein-coupled receptor (GPCR) 4 (Lgr4), which is one of the orphan GPCRs, were analyzed with the Lgr4 hypomorphic mutant mouse line (Lgr4Gt). This homozygous mutant had only one-tenth the normal transcription level; furthermore, 60% of them survived to adulthood. The homozygous male was infertile, showing morphologic abnormalities in both the testes and the epididymides. In the testes, luminal swelling, loss of germinal epithelium in the seminiferous tubules, and rete testis dilation were observed. Cauda epididymidis sperm were immotile. Rete testis dilation was due to a water reabsorption failure caused by a decreased expression of an estrogen receptor (ESR1) and SLC9A3 in the efferent ducts. Although we found differential regulation of ESR1 expression in the efferent ducts and the epididymis, the role of ESR1 in the epididymis remains unclear. The epididymis contained short and dilated tubules and completely lacked its initial segment. In the caput region, we observed multilamination and distortion of the basement membranes (BMs) with an accumulation of laminin. Rupture of swollen epididymal ducts was observed, leading to an invasion of macrophages into the lumen. Male infertility was probably due to the combination of a developmental defect of the epididymis and the rupture of the epithelium resulting in the immotile spermatozoa. These results indicate that Lgr4 has pivotal roles to play in the regulation of ESR1 expression, the control of duct elongation through BM remodeling, and the regional differentiation of the caput epididymidis.
developmental biology, epididymis, estradiol receptor, male reproductive tract, steroid hormone receptors
1Supported in part by KAKENHI (grant-in-aid for scientific research) in Priority Areas "Integrative Research Toward the Conquest of Cancer" from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a grant from the Osaka Foundation For the Promotion of Clinical Immunology; and a grant from the Pancreas Research Foundation of Japan.
Correspondence: 2FAX: 81 96 373 6599; e-mail: yamamura{at}gpo.kumamoto-u.ac.jp
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