Sertoli cell specific decline in NOR-1 leads to germ cell apoptosis and reduced fertility

The somatic component of seminiferous epithelium, the Sertoli cells (Sc) respond to Follicle stimulating hormone (FSH), and Testosterone (T) to produce factors which are necessary for germ cell (Gc) survival and differentiation. Infant Sc do not support spermatogenesis in spite of sufficient hormonal milieu, a situation similar to that found in male idiopathic infertility. Sc maturation during pubertal period involves expression of some genes which may be important for initiation of spermatogenesis. Analysis of differentially expressed genes, one by one, in infant and pubertal Sc might provide useful information about the regulation of spermatogenesis. DNA microarray based analysis of mRNA from 5-days (infant) and 12-days (pubertal) old rat Sc revealed increased expression of Nor-1 by pubertal Sc. NOR-1 is an orphan nuclear receptor involved in maintaining cellular homeostasis and disease. We generated transgenic mice using shRNA cloned under Pem (Rhox5) promoter which is activated at puberty in Sc. Such transgenic mice had reduced Nor-1 expression and increased Tgfβ1, Tgfβ3, and Smad3 expression. Moreover, an increase in β-catenin expression was observed in NOR-1 knockdown testes. High β-catenin in such transgenic mice was found to be associated with disruption of Sc maturation characterized by elevated expression of Anti Mullerian hormone, Cytokeratin 18, and Sox9. This disruption of Sc maturation resulted in Gc apoptosis. Such NOR-1 knockdown mice showed reduced sperm count and litter size. We report for the first time that NOR-1 plays a crucial role in regulating sperm count and male fertility.