Our paper on flexibility in the cellular encoding of sexual state in C. elegans is out today! Great work from @TheScientistHan, @LeighWexler (former @portmanlab graduate students) and Hayley Wnuk (current graduate student). Here’s a synopsis. #celegans cell.com/current-biolog… 1/
First: this is a story about biological sex, not gender. The latter is socially and culturally influenced and is deeply tied to self-identity. Humans have this; worms don’t. 2/
Biological sex is typically seen as a static, binary characteristic. It’s not hard to see why — most species have two distinct morphs that produce different types of gametes, and this state is often set by a binary sex-determining cue (e.g., sex chromosomes). 3/
Our new paper shows that, in the C. elegans nervous system, this simple model doesn’t hold. Instead, at a molecular level, the way sex is “represented” or “encoded” isn’t static or binary; rather, it’s dynamic and heterogeneous. First, some background. 4/
The primary sex-determining cue in C. elegans is the number of X chromosomes. A fertilized egg that has one X develops as a male. Two X’s, it becomes a hermaphrodite. There are no females in C. elegans; its hermaphrodites have female bodies but produce both sperm and eggs. 5/
Beautiful genetic studies done in the 1980s by Jonathan Hodgkin, Barbara Meyer, and others showed how the XX/XO cue determines sexual state. Through a complex molecular cascade, this signal regulates a single gene, tra-1, the “master regulator” of C. elegans sex. 6/
tra-1 encodes a CI/Gli transcription factor that is active in XX individuals but inactive in XO. Loss of tra-1 function “transforms” XX worms into fertile males, while hyperactivity of tra-1 converts XO worms into hermaphrodites (or even females). 7/
So, tra-1 acts to promote hermaphrodite/female-ness and repress male-ness. Genes regulated by tra-1 do the complex business of implementing sexual dimorphism and sex differences in development and physiology throughout the body. 8/
tra-1 has a minor role in the male gonad, but aside from that, this model says that tra-1 shouldn’t do anything in males. But work we’ve been doing on male behavioral flexibility for the past few years led us to wonder whether this was really the case. 9/
Classic experiments by Jonathan Lipton and Scott Emmons showed that adult C. elegans males will abandon a food source to search for mates. Hermaphrodites don’t do this. Interestingly, juvenile males don’t abandon food either, nor do starved adult males. 10/
Many mechanisms contribute to this behavioral flexibility. We identified one of them a few years ago: regulated expression of the food-associated chemoreceptor odr-10 in the AWA olfactory neurons helps modulate sensitivity to food. 11/
In adult hermaphrodites, odr-10 expression is high. But in adult males, odr-10 is strongly repressed. This dials down food sensitivity and helps prevent males from immediately returning to a food spot if they stray away. 12/
We showed previously that we could “sex-reverse” patterns of odr-10 expression and behavior by manipulating tra-1 activity in the nervous system. So, in adults, tra-1 acts in the nervous system to implement this sex difference. Completely consistent with the classic model. 13/
Interestingly, odr-10 can be activated in males under two known conditions. First, juvenile males (L3) express high odr-10, just like juvenile hermaphrodites. This makes sense, since neither sex needs to leave food to search for mates at this stage. 14/
Moreover, depriving adult males of food for a while causes them to activate odr-10 expression. This helps them focus on feeding; once they’re well-fed, odr-10 returns to its low baseline level and males go back to mate-searching mode. 15/
So, under these conditions, males adopt a pattern of odr-10 expression and behavior that’s more typical of hermaphrodites. We wondered whether this might arise by transient suppression of the male-typical “state.” If so, expression of odr-10 in males might require tra-1. 16/
Here we show that yes, it does! tra-1 is required for odr-10 expression in L3 males. In adult males, it’s required for the upregulation of odr-10 upon starvation. In both of these cases, tra-1 acts in the male nervous system (though probably not in AWA itself). 17/
.@TheScientistHan also carefully examined tra-1 protein. As expected, tra-1 protein was abundant and ~ubiquitous in adult hermaphrodites. But tra-1 wasn’t absent in males: it was present in a several neurons in adult males, and in even more in juvenile (L3) males. 18/
The decrease in tra-1 abundance in males from L3 to adult is controlled by the heterochronic pathway, a conserved developmental timer that acts in the C. elegans nervous system. Homologs of several genes in this pathway are implicated in the timing of puberty in mammals. 19/
Together, these findings demonstrate that tra-1 isn’t the simple on/off, hermaphrodite/male switch that we’ve imagined it to be. Neither its expression nor its function are limited to XX animals, and both of these are dynamic in males. 20/
A very nice companion paper from @ea_bayer and Oliver Hobert delves more deeply into the surprising complexity of tra-1 expression in both hermaphrodites and males. Excitingly, they find a role for the nuclear hormone receptor daf-12 in this process. cell.com/current-biolog… 21/
We still have a lot to learn about what tra-1 is doing in males and how its expression/function can be uncoupled from chromosomal sex. For now, our studies add to the growing appreciation that biological sex and sexual “state” are not simple binary features. 22/
Maybe this isn’t really so surprising after all: many species (ribbon eels, clownfish...) switch sex according to developmental or environmental cues. In Drosophila, recent work has found unexpected complexity in the way that master sexual regulators are themselves regulated. 23/
So, it could be that complexity in the specification of sexual state at the cellular level isn't the exception, but rather the rule. 24/
Finally, why? Sex determination pathways are extraordinarily plastic over evolutionary time. Maybe the forces that shape change in the specification of sex across species also have something to say about how it works at the cellular level. Thanks for reading! 25/
