摘要
Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples,and male infertility accounts for half of total infertility.Studies on genetically modified animal models have identifed lots of genes involved in the pathogenesis of male infertility.The underlying causes,however,remain largely unclear.In this study,we provide evidence that EMCIO,one subunit of endoplasmic reticulum (ER)membrane protein complex (EMC),is required for male fertility.EMC10 is significantly decreased in spermatozoa from patients with asthenozoospermia and positively associated with human sperm motility. Male mice lacking Emc10 gene are completely sterile.Emc10-null spermatozoa exhibit multiple defects including abnormal morphology,decreased motility,impaired capacitation,and impotency of acrosome reaction,thereby which are incapable of fertilizing intact or ZP-free oocytes.However,intracytoplasmic sperm injection could rescue this defect caused by EMC10 deletion. Mechanistically,EMC10 deficiency leads to inactivation of Na/K-ATPase,in turn giving rise to an increased level of intraceltutar Na^+ in spermatozoa,which contributes to decreased sperm motility and abnormal morphology.Other mechanistic investigations demonstrate that the absence of EMC10 results in a reduction of HCO3^- entry and subsequent decreases of both cAMP-dependent protein kinase A substrate phosphorylation and protein tyrosine phosphorytation.These data demonstrate that EMC10 is indispensable to mate fertility via maintaining sperm ion balance of Na^+ and HCO3^-,and also suggest that EMC10 is a promising biomarker for male fertility and a potential pharmaceutical target to treat male infertility.
基金
the National Basic Research Program (2014CB943103 to Y.Z.,2015CB943003 to Q.D.)
the National Natural Science Foundation of China (31471104 and 31671203 to Y.Z.,81370753 to Q.D.,81070647 and 81370936 to X.W.)
This work was also sponsored by grants from Shanghai Pujiang Program (16PJ1401700 to X.W.)
Science and Technology Commission of Shanghai Municipality (16140901200 to X.W.).
