Temperature-dependent sex determination is mediated by pSTAT3 repression of Kdm6b

Abstract

In many reptiles, including the red-eared slider turtle Trachemys scripta elegans (T. scripta), sex is determined by ambient temperature during embryogenesis. We previously showed that the epigenetic regulator Kdm6b is elevated at the male-producing temperature and essential to activate the male pathway. In this work, we established a causal link between temperature and transcriptional regulation of Kdm6b. We show that signal transducer and activator of transcription 3 (STAT3) is phosphorylated at the warmer, female-producing temperature, binds the Kdm6b locus, and represses Kdm6b transcription, blocking the male pathway. Influx of Ca2+, a mediator of STAT3 phosphorylation, is elevated at the female temperature and acts as a temperature-sensitive regulator of STAT3 activation.

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“…The signal transducer and activator of transcription-3 (STAT-3) was originally identified as a critical mediator of the IL-6-type cytokine signal pathway and described as an acute phase response factor (APRF) [1,2], which can operate as a transcription factor of various cytokines, interferons, hormones, and growth factors [3]. After dimerization, STAT-3 can transfer to the nucleus and act as a transcription activator.…”

Corticosterone does not have a role in temperature sex reversal in the central bearded dragon (Pogona vitticeps)

“…For example, the reciprocal regulation of calcium levels and reactive oxygen species have the potential to encode and transduce environmental stimuli and influence sexual outcomes (Castelli et al, 2020). Recent experimental evidence supports this hypothesis, with calcium levels found to regulate the epigenetic regulators of sex determination in a TSD turtle (Weber et al, 2020). Due to the apparent lack of a responsive stress axis during the temperature sensitive period in P. vitticeps , a biochemical and gonad‐autonomous sensor may be a better candidate for the biological transducer of environmental cues in ESD reptiles.…”

“…Temperature has the capacity to direct sexual outcomes in the absence of sex chromosomes, in combination with an underlying genetic predisposition or even in the presence of differentiated sex chromosomes (Sarre et al, 2004). The epigenetic effectors of ESD are becoming well characterized in reptiles (Deveson et al, 2017; Ge et al, 2018; Weber et al, 2020), but the biological sensory mechanism which receives and translates the environmental signal into a biological cue is not yet known (Georges & Holleley, 2018).…”

Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

“…Recent research led to the hypothesis that the cellular sensor initiating ESD is controlled by the balance of redox regulation and calcium (Ca 2+ ) signalling (CaRe) (13). The CaRe hypothesis proposes a link between CaRe sensitive cellular signalling and the highly conserved epigenetic processes that have been implicated in thermolabile sex (TSD and temperature sex reversal) (12,14–17). The CaRe hypothesis posits that in ESD systems a change in intracellular Ca 2+ (probably mediated by thermosensitive transient receptor potential TRP channels) and increased reactive oxygen species (ROS) levels caused by high temperatures, alter the CaRe status of the cell, triggering cellular signalling cascades that drive differential sex-specific expression of genes to determine sex.…”