Argue KJ, Neckameyer WS. Altering the sex determination pathway in Drosophila fat body modifies sex-specific stress responses. The stress response in Drosophila melanogaster reveals sex differences in behavior, similar to what has been observed in mammals. However, unlike mammals, the sex determination pathway in Drosophila is well established, making this an ideal system to identify factors involved in the modulation of sex-specific responses to stress. In this study, we show that the Drosophila fat body, which has been shown to be important for energy homeostasis and sex determination, is a dynamic tissue that is altered in response to stress in a sex and time-dependent manner. We manipulated the sex determination pathway in the fat body via targeted expression of transformer and transformer-2 and analyzed these animals for changes in their response to stress. In the majority of cases, manipulation of transformer or transformer-2 was able to change the physiological output in response to starvation and oxidative stress to that of the opposite sex. Our data also uncover the possibility of additional downstream targets for transformer and transformer-2 that are separate from the sex determination pathway and can influence behavioral and physiological responses.transformer; transformer-2; behavior; stress; sex differences SEX DIFFERENCES have been observed in the stress response in Drosophila (38,39), analogous to what has been described in mammals. Additional studies have suggested that underlying the different behavioral responses are distinct neuronal stressresponse circuits for males and females (2). These include changes in heart rate and several parameters of locomotor behavior (centrophobism, escape behavior, freezing, and changes in patterns of movement, which are analogous to stress-response behaviors described in mammals), which were assessed after starvation or oxidative stress, two stressors that have been linked to the development of psychiatric illnesses (34,46). It is likely that the mammalian stress response circuitry is also sex specific, based on differences in stress responses and susceptibility to stress-related pathologies (15,45). Drosophila thus provides an ideal model for the elucidation of factors modulating sexual dimorphism in the stress response.We used the genetic tractability of Drosophila to manipulate the sex determination pathway and assess the effect of changing the sexual milieu of the brain on the response to stress. Sex determination is Drosophila is a cell autonomous process, meaning that each cell "decides" whether it will be male or female based on the ratio of X-linked numerator genes [sisterless-a (sisA), sisterless-b (sisB), sisterless-c (sisC), and runt (run)] to an autosomal denominator gene [deadpan (dpn)] (6, 14, 17, 49, 54; reviewed in 44). In females, where the numerator to denominator ratio is 2:2, the resulting gene products are transcription factors that produce functional sex-lethal (SXL) protein (14,17,49,54). In females SXL produces a functional transformer ...