Functional Mechanism Of Nuclear Respiratory Factor NRF1 And Other Transcription Factors In Regulating Germ Cell Development

Germ cells pass genetic informations across generations in multicellular animals,and therefore are critical for continuation of species.Germ cells originate from the primordial germ cells(PGCs)during embryonic development.Followed by migration,sex determination,and meiosis,they finally develop into haploid gametes.The germ cell development is strictly regulated at transcriptional,metabolic,and epigenetic levels.Understanding the regulatory mechanisms of germ cell development is helpful to robustly induce germ cells formation in vitro and provides novel targets to treat infertility.In this study,we first focused on the roles of nuclear respiratory factor 1(NRF1)in PGC formation.NRF1 is a transcriptional regulator that mainly regulates mitochondrial energy production.We recently found that NRF1 also plays a role in spermatogenesis by directly regulating transcription of germ cell specific genes.To understand the functions of NRF1 in PGC formation,we established mouse embryonic stem cell(ESC)lines overexpressing a NRF1 transgene.Using ESC in vitro differentiationg system,we found that NRF1 overexpression promoted the formation of PGCs and enhanced the expression of germ cell-specific genes.Our data thus revealed a critical role of NRF1 in PGC development.Our pilot data suggest that bioenergetic preference changes during the differentiation of spermatogonial stem cells(SSCs).To understand the transcription regulation of metabolic changes during spermatogonial differentiation we predicted the transcription factors that regulate the enzymes in the key metabolic pathways,and analyzed their binding sites and expression changes.We identified four transcription factors: FOXD3,FOXL1,OCT1 and SOX5,which may play a role in regulating expression of metabolic enzymes during spermatogonial differentiation,thereby providing important clues for metabolic regulation in postnatal germ cell development.