DrosophilaSister-of-Sex-lethal reinforces a male-specific gene expression pattern by controllingSex-lethalalternative splicing

Abstract

In Drosophila, female development is governed by a single RNA-binding protein, Sex-lethal (Sxl), that controls the expression of key factors involved in dosage compensation, germline homeostasis and the establishment of female morphology and behaviour. Sxl expression in female flies is maintained by an auto-regulatory, positive feedback loop with Sxl controlling splicing of its own mRNA. Until now, it remained unclear how males prevent accidental triggering of the Sxl expression cascade and protect themselves against runaway protein production. Here, we identify the protein Sister-of-Sex-lethal (Ssx) as an inhibitor of Sxl auto-regulatory splicing. Sxl and Ssx have a comparable RNA-binding specificity and compete for binding to RNA regulatory elements present in the Sxl transcript. In cultured Drosophila cells, Sxl-induced changes to alternative splicing can be reverted by the expression of Ssx. Moreover, in adult male flies ablation of the ssx gene results in a low level of productive Sxl mRNA splicing and Sxl protein production in isolated, clonal cell populations. In sum, this demonstrates that Ssx safeguards male animals against Sxl protein production to reinforce a stable, male-specific gene expression pattern.

Sex-specific transcript diversity is regulated by a maternal transcription factor in earlyDrosophilaembryos

“…Functional Sxl protein is produced specifically in females because exon three in the sxl transcript contains a premature stop codon which is spliced out in females but retained in males (Haussmann et al 2016). Therefore, the Sxl protein is non-functional in males and becomes degraded (Salz and Erickson 2010; Moschall et al 2019). In females, Sxl protein inhibits the splicing of the msl2 transcript which prevents aberrant Msl2 expression and MSL complex formation in females.…”

Pseudo-RNA-Binding Domains Mediate RNA Structure Specificity in Upstream of N-Ras

“…In contrast, other targets show reduced binding after RNase treatment, showing that binding is likely mediated by RNA. One example for an RNA-dependent interaction is Sister-of-sex-lethal (Ssx), which is a homolog of Sxl, known to exhibit comparable msl-2 mRNA-binding activity while being incapable of engaging Unr directly ( Moschall et al., 2019 ). This consensus with previous studies further strengthens the reliability of our results.…”

Auto-regulatory feedback by RNA-binding proteins

“…Moreover, in many cases auto-regulatory pathways require additional co-regulators (Suissa et al, 2011; Kolesnikova et al, 2013), or inhibitory factors can antagonize autogenous feedback, e.g. by competition for the same RNA elements (Moschall et al, 2018). Control of the abundance or the activity of these co-factors or inhibitors provides an additional mechanism to adjust and fine-tune the steady-state levels of auto-regulatory RBPs.…”