Abstract
We demonstrate how RNA binding protein FOX-1 functions as a dose-dependent X-signal element to communicate X-chromosome number and thereby determine nematode sex. FOX-1, an RNA recognition motif protein, triggers hermaphrodite development in XX embryos by causing non-productive alternative pre-mRNA splicing of xol-1, the master sex-determination switch gene that triggers male development in XO embryos. RNA binding experiments together with genome editing demonstrate that FOX-1 binds to multiple GCAUG and GCACG motifs in a xol-1 intron, causing intron retention or partial exon deletion, thereby eliminating male-determining XOL-1 protein. Transforming all motifs to GCAUG or GCACG permits accurate alternative splicing, demonstrating efficacy of both motifs. Mutating subsets of both motifs partially alleviates non-productive splicing. Mutating all motifs blocks it, as does transforming them to low-affinity GCUUG motifs. Combining multiple high-affinity binding sites with the twofold change in FOX-1 concentration between XX and XO embryos achieves dose-sensitivity in splicing regulation to determine sex.
Highlights
Determining sex is one of the most fundamental developmental decisions that most organisms must make
Our prior experiments showed that overexpression of FOX-1 by itself is sufficient to repress endogenous xol-1 activity, causing XO embryos to adopt the hermaphrodite sexual fate and die from reduced X-chromosome expression triggered by binding of the dosage compensation complex (DCC) to the single X (Nicoll et al, 1997)
The xol-1(+) transgenes were expressed in XX animals at a somewhat higher level than the endogenous xol-1 gene: the seven XX array lines could only be maintained if both endogenous copies of fox-1 were wild type
Summary
Determining sex is one of the most fundamental developmental decisions that most organisms must make. The X:A signal determines sex by controlling the activity of its direct target, the master sex-determination switch gene xol-1 (XO lethal) (Figure 1; Carmi et al, 1998; Farboud et al, 2013; Meyer, 2018; Miller et al, 1988; Nicoll et al, 1997; Powell et al, 2005; Rhind et al, 1995). Xol-1 controls the choice of sexual fate and X-chromosome gene expression through the process of X-chromosome dosage compensation (Meyer, 2018; Miller et al, 1988; Rhind et al, 1995).
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