Estrogen Receptor beta 2 Oversees Germ Cell Maintenance and Gonadal Sex Differentiation in Medaka, Oryzias latipes

In vertebrates, estrogen receptors are essential for estrogen-associated early gonadal sex development. Our previous studies revealed sexual dimorphic expression of estrogen receptor beta 2 (ER beta 2) during embryogenesis of medaka, and here we investigated the functional importance of ER beta 2 in female gonad development and maintenance using a transgenerational ER beta 2-knockdown (ER beta 2-KD) line and ER beta 2-null mutants. We found that ER beta 2 reduction favored male-biased gene transcription, suppressed female-responsive gene expression, and affected SDF1a and CXCR4b co-assisted chemotactic primordial germ cell (PGC) migration. Co-overexpression of SDF1a and CXXR4b restored the ER beta 2-KD/KO associated PGC mismigration. Further analysis confirmed that curtailment of ER beta 2 increased intracellular Ca2+ concentration, disrupted intra- and extracellular calcium homeostasis, and instigated autophagic germ cell degradation and germ cell loss, which in some cases ultimately affected the XX female sexual development. This study is expected improve our understanding of germ cell maintenance and sex spectrum, and hence open new avenues for reproductive disorder management.