Nor1 and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis Using a Transgenic Rat Model

Male infertility is a global health concern, and many cases are idiopathic in nature. The development and differentiation of germ cells (Gcs) are supported by Sertoli cells (Scs). Differentiated Scs support the development of Gcs into sperm, and hence, male fertility. We previously reported on a developmental switch in Scs around 12 days of age onwards in rats. During the process of the differentiation of Scs, the differential expression of mitophagy-related genes and its role in male fertility are poorly understood. To address this gap, we evaluated the microarray dataset GSE48795 to identify 12 mitophagy-related hub genes, including B-Cell Leukemia/Lymphoma 2 (Bcl2) and FBJ murine osteosarcoma viral oncogene homolog (Fos). We identify Neuron-derived orphan receptor 1 (Nor1) as a potential mitophagy-related gene of interest due to its strong regulatory association with two hub genes, Bcl2 and Fos, which were differentially expressed during Sc maturation. To validate this finding, we generated a transgenic rat model with the Sc-specific knockdown of Nor1 during puberty. A functional analysis showed impaired spermatogenesis with reduced fertility in these transgenic rats. Our findings suggest that Nor1 may be an important mitophagy-related gene regulating the function of Scs and thereby regulating male fertility.