Twin Gene Functions In The Maintenance And Differentiation Of The Ovarian Germline Stem Cell Lineage In Drosophila

The central question in stem cell regulation is how the balance between self-renewal and differentiation is achieved at the molecular level. In the Drosophila ovary, germline stem cells(GSCs) are an effective system for studying self-renewal and differentiation at the molecular and cellular level. In this study, we show that Twin is required intrinsically to control GSC self-renewal by preventing DNA damage and maintaining E-cadherin expression, and also works with Bam to promote germ cell differentiation. Twin is the Drosophila CCR4 homolog, a component of the highly conserved CCR4-NOT deadenylase complex for regulating mRNA stability and translation. Twin, along with the other CCR4-NOT components, is required intrinsically to maintain GSC self-renewal at least by two distinct mechanisms. Twin positively regulates E-cadherin expression in GSCs, strengthening the GSC-niche interaction. Twin also represses the activities of transposable elements in GSCs via direct interaction with piRNA components Aubergine and Ago3, thus preventing Chk2-dependent DNA damage-evoked checkpoint activation. Twin associates with the differentiation-promoting Bam-Bgcn complex in GSC progeny to promote GSC lineage differentiation by promoting Bam expression and repressing Nanos expression. Therefore, this study demonstrates that Twin controls GSC selfrenewal by maintaining E-cadherin expression and genome stability by working with other CCR4-NOT components, and promotes GSC progeny differentiation by working with Bam. This study has also suggested that Twin performs opposite biological roles in GSCs and their progeny by forming distinct protein complexes.