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. Author manuscript; available in PMC: 2025 Nov 18.
Published in final edited form as: Genetics. 2026 Jan 7;232(1):iyaf239. doi: 10.1093/genetics/iyaf239

Dopamine production in the central nervous system is important for follicle survival and interacts with genetic background and a high sugar diet during Drosophila oogenesis

Rodrigo Dutra Nunes 1,2, Daniela Drummond-Barbosa 1,2,*
PMCID: PMC12621419  NIHMSID: NIHMS2122626  PMID: 41192415

Abstract

Unhealthy diets, obesity, and low fertility are associated in Drosophila and humans. We previously showed that a high sugar diet, but not obesity, reduces Drosophila female fertility owing to increased death of newly formed germline cysts and vitellogenic follicles. Drosophila strains carrying mutations in the yellow (y) and white (w) pigmentation genes are routinely used for investigating the effects of high sugar diets, but it has remained unclear how this genetic background interacts with high sugar. Here, we show that the loss of y function is responsible for the high sugar diet-induced death of early germline cysts and vitellogenic follicles previously observed in y w mutant females. Dopamine supplementation prevents follicle death in y mutants on a high sugar diet. Conversely, severe dopamine imbalance or lack of dopamine production in the central nervous system causes follicle death regardless of diet or genetic background, while early germline cyst survival does not depend on dopamine. Our findings are broadly relevant to our understanding of how the effects of unhealthy diets might differ depending on genetic factors and highlight a key connection between dopamine metabolism in the central nervous system and ovarian follicle survival.

Keywords: high sugar diet, germline, dopamine, oogenesis, follicle death, yellow

ARTICLE SUMMARY

Unhealthy diets, obesity, and reduced fertility are associated in Drosophila and humans. Recently, we showed that a high sugar diet induces ovarian follicle death and reduces Drosophila fertility independently of obesity. Here, we report that follicle degeneration induced by a high sugar diet depends on genetic background in connection with dopamine in the central nervous system. We also show that severe dopamine imbalance increases follicle death regardless of diet or genetic background. These findings are broadly relevant to our understanding of how the effects of unhealthy diets might differ depending on genetic factors and highlight an important connection between dopamine metabolism and oogenesis.

INTRODUCTION

High sugar consumption and obesity are associated with negative health outcomes, including infertility (Stanhope 2016; Faruque et al. 2019; Malik and Hu 2022; Huang et al. 2023). In Drosophila, other groups had shown that a high sugar diet leads to obesity and reduced female fertility (Morris et al. 2012; Brookheart et al. 2017), but it had remained unclear if obesity itself had direct negative effects on oogenesis. More recently, we showed that a high sugar diet, but not obesity, causes decreased fertility in Drosophila (Nunes and Drummond-Barbosa 2023). However, the underlying mechanisms remained largely unknown.

Drosophila is a well-established genetic model for the study of oogenesis processes (Doherty et al. 2022; Spradling et al. 2022; Giedt and Tootle 2023) and has evolutionarily conserved metabolic responses to high sugar diets (Na et al. 2013; Brookheart et al. 2017; May et al. 2020; Sanz et al. 2022; Nunes and Drummond-Barbosa 2023; Yang et al. 2023). Each female has a pair of ovaries subdivided into ~15 ovarioles with an anterior germarium followed by developing follicles (also known as egg chambers) (Fig. 1A). Follicles, composed of a 16-cell germline cyst (i.e., one oocyte and 15 nurse cells) surrounded by a monolayer of follicle cells, are produced within the germarium. Newly formed follicles continue to develop through 14 discernable stages to form mature oocytes. Once the follicle reaches stage 8, the oocyte begins taking up yolk, marking the onset of vitellogenesis, a resource- and energy-intensive process that is highly regulated in response to physiological changes (Drummond-Barbosa 2019). In particular, we showed that vitellogenic follicles (as well as early germline cysts within the germarium) die at higher rates in females on a high sugar diet compared to those on a control diet (Nunes and Drummond-Barbosa 2023). This increase in follicle death on a high sugar diet is reminiscent of the increased follicle atresia observed in the ovaries of rats maintained on high fat-high sugar diets (de Melo et al. 2021; Rejani et al. 2022; Demirel et al. 2024), suggesting that conserved mechanisms could be at play.

Fig. 1. High sugar diet-induced vitellogenic follicle degeneration requires loss of yellow function.

Fig. 1.

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(A) Drosophila ovariole diagram showing the germarium followed by developing follicles (also known as egg chambers). Each follicle is composed of a 16-cell germline cyst (one oocyte and 15 supportive nurse cells) surrounded by follicle cells. Vitellogenic stages are characterized by the presence of yolk in the oocyte and mature oocytes have a fully formed dorsal appendage. (B–E) Single confocal sections of ovaries from y* ac* w1118 females maintained on control (B,C) or high sugar (D,E) diets for 7 days. (C,E) Insets showing part of ovarioles from (B,D), respectively, with anterior to the left and posterior to the right. Cleaved Dcp-1 (red) labels apoptotic cells; DAPI (white) labels nuclei. (Anti-cleaved Dcp-1 antibodies also label dorsal appendages.) Dying vitellogenic follicles (indicated by arrowheads) are recognized by the presence of pyknotic nuclei and cleaved Dcp-1. Scale bars: 50 μM (B,D); 200 μM (D,E). (F,G) Frequencies of ovarioles containing dying vitellogenic follicles from females of the indicated genotypes maintained on control (black bars) or high sugar (red bars) diets. Numbers of ovarioles analyzed are shown inside bars. Data shown as mean±s.e.m. from two independent experiments. *P<0.05, **P<0.01, ****P<0.0001; Chi-square test. (See Supplementary Data File S1 for raw data.)

Genetic background, among other factors, influences diet-related phenotypes in organisms ranging from Drosophila to humans. For example, humans have high interpersonal variability in postprandial blood glucose levels (Zeevi et al. 2015); genetic predispositions influence the association between the consumption of sugar-sweetened beverages and adiposity (Haslam et al. 2018); 10-30% of obese individuals maintain healthy metabolic profiles (Schulze and Stefan 2024); and homozygosity of a specific variant of sucrase-isomaltase improves the metabolic health of adult cohorts in Greenland (Andersen et al. 2022). In mice, diet interacts with genetic background to affect weight gain and metabolic parameters (Reed et al. 2024), while in Drosophila genetic background affects the tolerance of developing larvae and pupae to high levels of dietary macronutrients (Havula et al. 2022).

Drosophila studies involving high sugar diets (Morris et al. 1999; Brookheart et al. 2017; Nunes and Drummond-Barbosa 2023) have routinely used flies carrying mutations in the yellow (y) and white (w) genes, which affect cuticle and eye pigmentation, respectively. w encodes an ABCG transporter (Mackenzie et al. 1999), while y has unknown molecular function but is required for the production of melanin from dopamine during insect cuticle development (Wittkopp et al. 2002; Drapeau 2003). y and w mutations are common in the Drosophila field because having them in the background facilitates the recognition of transgenes containing wildtype y and/or w “markers” (St Johnston 2013). It has remained unclear, however, whether the y w genetic background might affect how adult flies respond to high sugar diet, including their reduced female fertility phenotype.

In this study, we show that y mutation sensitizes females to a high sugar diet in a dopamine-dependent manner. Specifically, y mutant females have a higher frequency of vitellogenic follicle death on a high sugar diet, while wildtype Canton-S or Oregon-R-C females or y mutants carrying a genomic rescue wildtype y transgene have no increase in follicle death in response to high sugar. Like y mutation, disruption of other genes in the melanin/sclerotin biosynthetic pathway (expected to alter dopamine levels) also leads to increased vitellogenic follicle death on a high sugar diet; conversely, dopamine supplementation prevents high sugar diet-induced follicle death in y mutant females. Lack of dopamine production in the central nervous system (CNS) causes vitellogenic follicle death regardless of diet, and this phenotype is partially reversed by dopamine supplementation in adults. Finally, we show that severe increase or decrease in dopamine levels can cause follicle death regardless of diet or genetic background. These findings uncover a new role for y in sensitizing females to high sugar and an important connection between dopamine metabolism and oogenesis, providing a foundation for future research on the underlying cellular and molecular mechanisms. They also contribute more broadly to our understanding of how the effects of unhealthy diets differ depending on genetic factors.

MATERIALS AND METHODS

Drosophila strains and culture conditions

Drosophila stocks were maintained at 22°C on standard medium composed of 5.8% v/v unsulfured cane molasses (Sweet Harvest Feeds), 4.64% w/v yellow cornmeal (Quaker), 1.74% w/v active dry yeast (Red Star), 0.93% w/v agar (Apex BioResearch Products), 1.05% Tegosept (Apex Chemicals) and 0.36% propionic acid (Apex Chemicals). (Note: The concentration of 5.8% molasses in our standard medium corresponds to ~5% sugar, mostly sucrose.) The following strains are described in FlyBase (Öztürk-Çolak et al. 2024): Canton-S (BDSC:64349), Oregon-R-C (BDSC:5), y* ac* w1118 (Spradling 1986; Nunes and Drummond-Barbosa 2023), y1 w1 (BDSC:1495), y1 w1118 (BDSC:6598), w1 (BDSC:145), w1118 (BDSC:3605), DdcDE1 (BDSC:3168), PPO2Δ PPO1Δ PPO31 (BDSC:68387) e1 (BDSC:1658), and t1 (BDSC:130). y1 (BDSC:169) is a null allele (Geyer et al. 1990), and the BAC transgene DP(1;3)DC006 (BDSC:30217) (Venken et al. 2010) contains a wildtype copy of y (Öztürk-Çolak et al. 2024). w*;ple2 P{ple+t20}attP2 and w*;ple2 P{pleFS}attP2 (kind gifts from Jay Hirsch) have been previously described: ple2 is a null allele; P{ple+t20}attP2 is a 20-kb genomic rescue transgene encompassing ple that fully rescues ple2; and P{pleFS}attP2 is a similar rescue transgene in which two compensating frameshift point mutations disrupt the translation of CNS-specific ple isoforms but not of the hypodermal isoform for generation of brain dopamine-deficient flies (Cichewicz et al. 2017). For all experiments, newly eclosed flies raised on standard medium at 22°C were incubated at 25°C with 70% humidity and 12:12 light-dark cycle either on standard control medium (control diet) or standard medium with added sucrose (~32% sugar content; high sugar diet) at a density of 10-15 couples per vial, flipped every 2 days, for 7 days. Vials for experiments were stored at 4°C and used within a month. Vials with added drugs were prepared fresh, stored at 4°C protected from light and used within a week. Differences in food batches can lead to variability from experiment to experiment.

yellow rescue experiments

For y rescue experiments, y1 homozygous with or without the genomic rescue transgene were generated from the same cross. First, w1118;;DP(1;3)DC006 males were crossed to y1 virgin females to generate y1;;DP(1;3)DC006/+ males. Then, y1;;DP(1;3)DC006/+ males were crossed to y1 virgin females to generate y1 females (recognizable by their “yellow” cuticle) and sibling y1;;DP(1;3)DC006/+ females (“rescued y”, which had wildtype cuticle pigmentation). Similar crosses were performed for rescue experiments using y1 w1118 females.

Drug-feeding experiments

For drug feeding experiments, dopamine (Dopamine hydrochloride H8502, Sigma), L-DOPA (3-4-Dihydroxy-L-phenylalanine D9628, Sigma) and 3IY (3-Iodo-L-tyrosine I8250, Sigma) were directly mixed into melted medium at the indicated final concentrations, while carbidopa (S-(−)-Carbidopa C1335, Sigma) was dissolved in water at 10-fold of the final concentration and then mixed with melted medium. All drug-supplemented media were kept protected from light at 4°C for up to 1 week prior to use, as previously described (Cichewicz et al. 2017).

Tissue staining, “flower mounting,” and microscopy

Ovaries were dissected in Grace’s Insect Medium (BioWhittaker) without teasing ovarioles apart. Samples were fixed for 15 minutes at room temperature in fixing solution [5.3% paraformaldehyde (Ted Pella) in Grace’s medium] and then rinsed and washed three times for 15 minutes each in PBST [0.1% Triton X-100 in PBS (10 mM NaH2PO4/NaHPO4, 175 mM NaCl, pH 7.4)]. Samples were blocked for 3 hours at room temperature in blocking solution [5% normal goat serum (MP Biochemicals) plus 5% bovine serum albumin (Sigma-Aldrich) in PBST] and then incubated overnight at 4°C in 1:100 rabbit anti-cleaved Dcp-1 (Cleaved Drosophila Dcp-1 (Asp215) 9578, Cell Signaling) in blocking solution. Ovaries were washed and incubated with 1:400 goat anti-rabbit conjugated to Alexa Fluor 568 (A-11011, Molecular Probes/Invitrogen) at room temperature and protected from light, as described (Armstrong and Drummond-Barbosa 2018). Samples were washed (protected from light) and stored in Vectashield containing DAPI (4′,6-diamidino-2-phenylindole, a fluorescent stain specific to DNA) (Vector Laboratories) overnight. Whole ovaries (“flower mounting”) were partially teased to keep all ovarioles attached to the main oviduct of each ovary and mounted on glass slides with coverslips. Data were collected using a Zeiss AxioImager-A2 fluorescence microscope or Zeiss LSM900 confocal microscope.

Quantification of dying vitellogenic follicles and early germline cysts

All degenerating vitellogenic follicles have pyknotic nuclei and cleaved Dcp-1 staining, which are not present in healthy vitellogenic follicles. Dying early germline cysts were identified based on Dcp-1 staining. All experiments were performed in two independent replicates with ovaries from multiple females (using only one ovary per female) per genotype and/or condition for each replicate. Statistical analysis was performed using Chi-square test of combined results from all ovarioles in both replicates (Supplementary Data File S1), which is the most appropriate statistical test for comparing if observed frequencies differ from expected frequencies of categorial variables (i.e., dying vitellogenic follicle/early germline cysts present versus absent) (Xu et al. 2010). However, the graphs are plotted using the average of percentages per ovary to convey reproducibility from ovary to ovary and among experimental replicates (i.e. mean ± SEM).

RESULTS

The increase in vitellogenic follicle degeneration induced by a high sugar diet depends on genetic background

We previously showed that a high sugar diet, but not obesity, causes increased degeneration of vitellogenic follicles in y* ac* w1118 Drosophila females (Nunes and Drummond-Barbosa 2023). To determine if this high sugar effect depends on y and w mutations in the genetic background, we examined the ovarian response to a high sugar diet in y1 w1118 and y1 w1 females, in addition to two wildtype strains, Canton-S and Oregon-R-C (Öztürk-Çolak et al. 2024). Females raised on a standard control diet were maintained on either control or high sugar diets for 7 days and their ovaries analyzed using the cleaved Dcp-1 apoptosis marker and pyknotic nuclei to identify dying follicles (Fig. 1B–E), as previously described (Armstrong and Drummond-Barbosa 2018; Nunes and Drummond-Barbosa 2023). As expected, a high sugar diet (compared to the control diet) led to increased death of vitellogenic follicles (Fig. 1F) in y* ac* w1118 females. A similar response to high sugar was observed in y1 w1118 and y1 w1 females (Fig. 1F and Fig. S1). By contrast, although wildtype Canton-S and Oregon-R-C females had different baseline levels of vitellogenic follicle death, a high sugar diet had no effect compared to a control diet in these females (Fig. 1F and Fig. S1), showing that increased follicle degeneration in response to a high sugar diet depends on the genetic background.

The increase in vitellogenic follicle degeneration induced by a high sugar diet requires loss of yellow function

We next tested y and w mutations individually for a role in sensitizing vitellogenic follicles to a high sugar diet. In homozygous null w1 or strong hypomorphic w1118 females, there was no increase in the percentage of ovarioles with dying vitellogenic follicles in response to a high sugar diet (Fig. 1G). By contrast, homozygous null y1 females showed a significant increase in vitellogenic follicle death on a high sugar diet compared to a control diet, and this phenotype was rescued by a genomic rescue transgene carrying a wildtype copy of y (Fig. 1G and Fig. S1). We conclude that mutation of y sensitizes females to a high sugar diet, leading to increased vitellogenic follicle death.

Mutations in melanin/sclerotin pathway genes increase vitellogenic follicle degeneration on a high sugar diet

The y gene is required for the production of black melanin from dopamine, contributing to the pigmentation pattern of Drosophila adult cuticle and larval mouth parts (Nash and Yarkin 1974; Walter et al. 1996). Although the molecular function of Yellow remains largely unknown, the melanin biosynthesis pathway is well characterized in Drosophila (Massey and Wittkopp 2016; Sugumaran and Barek 2016) (Fig. 2A, top). Initially, tyrosine is converted to 3,4-dihydroxyphenylalanine (Dopa) by tyrosine hydroxylase (encoded by pale [ple]), and Dopa is decarboxylated into dopamine by Dopa decarboxylase (encoded by Ddc). Dopamine can then be converted into different types of pigments. For example, extracellular phenol oxidases (such as those encoded by Prophenoloxidase 1 [PPO1], PPO2, and PPO3) generate black melanin (as part of a yellow-dependent pathway) and brown melanin. Dopamine can also be linked to β-alanine by the product of ebony (e) to form β-alanyl dopamine (NBAD), which is then polymerized into yellow-tan sclerotin by phenol oxidases; NBAD can also be converted back into dopamine by the hydrolase encoded by tan (t). Phenol oxidases also contribute to the production of the colorless polymer N-acetyl dopamine sclerotin from dopamine, and Ddc has been proposed to produce black melanin directly from Dopa (Massey and Wittkopp 2016; Sugumaran and Barek 2016). In addition to being generated in hypodermal cells as a precursor for melanin (Massey and Wittkopp 2016; Sugumaran and Barek 2016), dopamine is also produced in the CNS, where it functions as a neurotransmitter (Karam et al. 2020) (Fig. 2A, bottom).

Fig. 2. Mutations in dopamine/melanin/sclerotin pathway genes increase vitellogenic follicle degeneration on a high sugar diet.

Fig. 2.

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(A) Simplified diagram of the dopamine/melanin/sclerotin pathway. The top panel represents pathway in the hypodermis and cuticle (see text for details). The bottom panel illustrates pathway in the CNS, where dopaminergic neurons produce dopamine that is typically released in the synaptic cleft to activate post synaptic neurons. Dopamine remaining in the synaptic cleft is absorbed by glial cells and converted into NBAD by the enzyme encoded by e. NBAD is transported to the dopaminergic neuron, where the product of t converts it to dopamine. (B) Frequencies of ovarioles containing dying vitellogenic follicles from females of the indicated genotypes maintained on control (black bars) or high sugar (red bars) diets. Numbers of ovarioles analyzed are shown inside bars. Data shown as mean±s.e.m. from two independent experiments. ***P<0.001, ****P<0.0001; Chi-square test. (See Supplementary Data File S1 for raw data.)

To investigate if mutations in other components of the melanin/sclerotin biosynthesis pathway can lead to death of vitellogenic follicles on a high sugar diet, we tested females homozygous for hypomorphic DdcDE1, t1, or e1 alleles, as well as triple PPO2Δ PPO1Δ PPO31 homozygous females. As expected, y1 mutant females showed increased death of vitellogenic follicles in response to a high sugar diet (Fig. 2B and Fig. S1). Although the baseline frequency of ovarioles showing vitellogenic follicle death on the control diet differed across genotypes, in all cases there was a significant increase in vitellogenic follicle death on a high sugar diet (Fig. 2B). Considering the known roles of pigmentation genes in dopamine metabolism (Walter et al. 1996; Takahashi 2013) (Fig. 2A), these results raised the possibility that changes in dopamine levels might contribute to the increased death of vitellogenic follicles on a high sugar diet in these mutant females.

Decreased dopamine levels increase vitellogenic follicle death in y1 females on a high sugar diet

In mammals, intermittent sugar intake causes brain dopamine release (Avena et al. 2008; Jacques et al. 2019); however, other studies have shown that both long-term sugar consumption and obesity result in low basal levels of dopamine in specific regions of the brain (Wang et al. 2001; Rada et al. 2005; Avena et al. 2008; Kravitz et al. 2016; Jacques et al. 2019; Wallace and Fordahl 2022). Consistent with these findings, male fruit flies fed a high sugar diet have decreased dopaminergic neuronal responses (May et al. 2020). We therefore hypothesized that maintaining females on a high sugar diet might lower their dopamine levels, leading to interactions with mutations in melanin/sclerotin pathway genes.

To test this hypothesis, we asked if dietary dopamine supplementation was sufficient to suppress the negative effects of a high sugar diet on the ovaries of y1 females (Fig. 3A). y1 females on a high sugar diet supplemented with 5 mg/mL dopamine had a significantly lower frequency of ovarioles containing dying vitellogenic follicles (~15%) than y1 females on a high sugar diet alone (~40%). Conversely, in y1 females on a high sugar diet containing a tyrosine hydroxylase inhibitor, 3-Iodo-L-tyrosine (3IY; 1.25 mg/mL) to inhibit dopamine production (Cichewicz et al. 2017), the frequency of ovarioles with dying vitellogenic follicles remained elevated (Fig. 3A). These results suggest that low dopamine levels and/or signaling underlie the effects of a high sugar diet in y1 females. Considering the role of y in the synthesis of melanin from dopamine (Fig. 2A)—which might at first glance suggest that y1 mutants would have higher levels of dopamine—our results also suggest a more complex role for yellow in dopamine metabolism and/or signaling.

Fig. 3. Dopamine supplementation suppresses vitellogenic follicle death in y1 females on a high sugar diet.

Fig. 3.

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(A,B) Frequencies of ovarioles containing dying vitellogenic follicles from y1 females maintained on a high sugar diet with (+) or without (−) dopamine (5 mg/mL) or 3IY (1.25 mg/mL) (A) or L-DOPA (1 mg/mL) plus Carbidopa (0.05 mg/mL) (B). Numbers of ovarioles analyzed are shown inside bars. Data shown as mean±s.e.m. from two independent experiments. *P<0.05, ****P<0.0001; Chi-square test. (See Supplementary Data File S1 for raw data.)

Dopamine production in the CNS is required for follicle survival regardless of diet

To address whether the source of dopamine relevant for vitellogenic follicle survival in y1 mutants is the CNS or hypodermal cells underlying the cuticle, we first selectively increased dopamine production in the CNS but not in peripheral tissues using a well-established pharmacological approach (Cichewicz et al. 2017). Specifically, it was previously shown, based on behavioral effects, that feeding the dopamine precursor L-DOPA does not induce dopamine synthesis in the CNS. However, combining L-DOPA with carbidopa (a Ddc inhibitor that does not cross the blood-brain barrier; see Fig. 2A) prevents L-DOPA from being converted to dopamine in peripheral tissues, thereby allowing more L-DOPA to cross the blood-brain barrier and reach the CNS (Cichewicz et al. 2017). Similar to the results from dopamine feeding (Fig. 3A), y1 females on a high sugar diet containing L-DOPA (1 mg/mL) plus carbidopa (0.05 mg/mL) had a lower frequency of dying vitellogenic follicles than females without these drugs (Fig. 3B). These results suggested the CNS as an important source of dopamine for vitellogenic follicle survival on a high sugar diet.

To directly test whether CNS dopamine production is important for vitellogenic follicles, we took advantage of an established CNS dopamine-deficient Drosophila model—referred to as “brain dopamine-deficient flies” (Cichewicz et al. 2017). In this model, homozygous ple2 null females carry either of two genomic rescue transgenes. In control females, the genomic rescue transgene has a wildtype copy of ple, which restores expression of all tyrosine hydroxylase isoforms (Fig. 4A). Brain dopamine-deficient females have a modified genomic rescue transgene in which frameshift point mutations in ple specifically disrupt the translation of CNS-specific isoforms of tyrosine hydroxylase while preserving the hypodermal isoform (Fig. 4A). While control females on a high sugar diet had low levels of dying vitellogenic follicles (Fig. 4B), brain dopamine-deficient females had a significant increase in the frequency of ovarioles with degenerating vitellogenic follicles (Fig. 4B). Similar results were obtained when similar experiments were conducted on a normal diet (Fig. 4C). These findings indicate that CNS dopamine production is important for the survival of vitellogenic follicles regardless of diet. They are also consistent with the observation that e1 and DdcDE1 mutants have increased vitellogenic follicle death on a high sugar diet (Fig. 2B)—loss of e function in glial cells has been shown to reduce dopamine production by brain neurons (Pantalia et al. 2023), while DdcDE1 homozygous have ~5% dopa decarboxylase activity in the CNS compared to ~50% in the hypodermis at pupariation (Bishop and Wright 1987).

Fig. 4. Brain dopamine protects vitellogenic follicles from death on a high sugar diet.

Fig. 4.

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(A) Diagram of brain dopamine-deficient and control flies. The gene ple encodes three mRNA isoforms: ple-RA is expressed in hypodermal cells involved in cuticle formation, while ple-RB and ple-RC are expressed in the CNS. Females homozygous for the null ple2 allele and carrying the wildtype genomic rescue transgene P{ple+t20}attP2 are fully rescued (Control), while ple2 homozygous carrying a similar transgene with mutations specifically disrupting the CNS isoforms, P{pleFS}attP2, only express the hypodermal isoform (Brain-dopamine deficient) (Cichewicz et al. 2017). (B-E) Frequencies of ovarioles containing dying vitellogenic follicles from females of the indicated genotypes maintained on a high sugar diet (B,D,E) or control diet (C) for 7 days. In (D,E), females were maintained on a high sugar diet with (+) or without (−) dopamine (5 mg/mL) (D) or L-DOPA (1 mg/mL) (E). Numbers of ovarioles analyzed are shown inside and/or above bars. Data shown as mean±s.e.m. from two independent experiments. *P<0.05, ****P<0.0001; Chi-square test. (See Supplementary Data File S1 for raw data.)

Interestingly, although dopamine is not thought to cross the blood–brain barrier in Drosophila (Cichewicz et al. 2017) or mammals (Calne et al. 1969; Cotzias et al. 1969), dopamine dietary supplementation partially suppressed the increased death of vitellogenic follicles in brain dopamine-deficient females (Fig. 4D). Importantly, L-DOPA supplementation—which should increase dopamine production in peripheral tissues in the absence of the carbidopa Ddc inhibitor (Cichewicz et al. 2017)—did not suppress vitellogenic follicle death (Fig. 4E). Based on these findings, we speculate that dopamine produced in the CNS is released into the hemolymph as a neurohormone to modulate vitellogenic follicle survival. In support of this conjecture, previous studies have shown that neuronal-specific manipulations can drastically alter the levels of dopamine present in Drosophila hemolymph and mammalian blood (Goldstein and Holmes 2008; Zhao et al. 2010).

y but not dopamine influences early germline cyst survival on a high sugar diet

A high sugar diet also increases early germline cyst death in y* ac* w1118 females (Nunes and Drummond-Barbosa 2023), and we wondered if a specific genetic background and/or dopamine is also required for this effect. y1 w1118, y1 w1, and y1 females maintained on a high sugar diet for 7 days had a higher frequency of germaria with dying germline cysts than those maintained on a control diet (Fig. 5A–C), and the early germline cyst death of y1 w1118 females could be rescued by a genomic transgene carrying a wildtype copy of y (Fig. 5D). pointing to a similar connection between this phenotype and loss of y function. Among dopamine/melanin/sclerotin pathway genes, however, only PPO2Δ PPO1Δ PPO31—but not DdcDE1, e1 or t1—females had a high sugar diet-induced increase in early germline cyst death, suggesting that this phenotype is independent of dopamine (Fig. 5C). Accordingly, brain dopamine-deficient females and their controls have similar frequencies of germaria showing early germline cyst death (Fig. 5E). We conclude that y and PPO genes function through a dopamine-independent mechanism to affect early germline cyst survival. Notably, PPOs have complex roles in immunity (Zdybicka-Barabas et al. 2025), suggesting potential mechanisms to explore in the context of high sugar diet and early germline cysts.

Fig. 5. Disruption of dopamine production does not cause early germline cyst death.

Fig. 5.

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(A,B) Single confocal sections of germaria from y1 females maintained on control (A) or high sugar (B) diets for 7 days. Cleaved Dcp-1 (green) labels apoptotic cells; Vasa (magenta) labels germline; DAPI (white) labels nuclei. Dying early germline cysts (indicated by arrowhead) are recognized by the presence of cleaved Dcp-1. Scale bar: 10 μM. (C-E) Frequencies of ovarioles containing dying early germline cysts from females of the indicated genotypes maintained on control (black bars) or high sugar (red bars) diets. Numbers of ovarioles analyzed are shown inside or above bars. Data shown as mean±s.e.m. from two independent experiments. *P<0.05, **P<0.01, ****P<0.0001; Chi-square test. (See Supplementary Data File S1 for raw data.)

Severe dopamine imbalance causes follicle death regardless of diet or genetic background

Our results indicated that dopamine is important for the survival of egg chambers (but not early germline cysts), so we next investigated the effects of manipulating dopamine levels in wildtype females. We first tested if dopamine excess or deficit would affect follicle death in wildtype Canton-S females on a high sugar diet supplemented with dopamine (5 mg/mL) or 3IY (1.25 mg/mL), respectively. There were no significant effects at these concentrations (Fig. 6A). Therefore, we fed them higher doses of dopamine (20 mg/mL) or 3IY (3 mg/mL). Canton-S females had elevated levels of vitellogenic follicle death upon stronger inhibition of dopamine synthesis, while there was no effect of elevated dopamine (Fig. 6B). On a control diet, Canton-S females became sensitive to high dopamine supplementation and were also sensitive to high doses of 3IY (Fig. 6B). These results suggest that either excess or reduced dopamine levels cause vitellogenic death, and they are also consistent with endogenous dopamine levels being higher on control relative to high sugar diets.

Fig. 6. Severe decrease or increase in dopamine levels causes follicle death regardless of diet or genetic background.

Fig. 6.

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(A–C) Frequencies of ovarioles containing dying vitellogenic follicles from Canton-S (A,B) or Oregon-R-C (C) females maintained on high sugar (red bars) or control (black bars) diets with or without dopamine [5 mg/mL in (A); 20 mg/mL in (B,C)] or 3IY [1.25 mg/mL in (A); 3 mg/mL in (B,C)] for 7 days. Numbers of ovarioles analyzed are shown inside bars. Data are shown as mean±s.e.m. from two independent experiments. **P<0.01, ***P<0.001, ****P<0.0001; Chi-square test. **P<0.01. (See Supplementary Data File S1 for raw data.) (D) Working model for dopamine imbalance in different contexts causing vitellogenic follicle death. Dopamine levels in the homeostatic range (top; e.g., in wildtype females regardless of diet; in y1 females on the control diet) promote vitellogenic follicle survival. The frequency of vitellogenic follicle degeneration increases significantly when dopamine levels fall below (middle; e.g., in y1 females on a high sugar diet, in brain dopamine-deficient females, or in wildtype females treated with a high dose of 3IY in specific diets) or above (bottom; e.g., wildtype females treated with a high dose of dopamine in specific diets).

We also tested these pharmacological manipulations in wildtype Oregon-R-C females, which have higher basal levels of follicle death on both diets relative to Canton-S (Fig. 1F). In Oregon-R-C females, supplementation with dopamine (20 mg/ml) reduced vitellogenic follicle death on a high sugar diet, while inhibition of dopamine synthesis with 3IY (3 mg/ml) had no effect (Fig. 6C), suggesting that Oregon-R-C females might have lower levels of dopamine than Canton-S on a high sugar diet. On a control diet, Oregon-R-C females had increased levels of follicle death in response to either high dopamine supplementation or strong inhibition of dopamine synthesis (Fig. 6C), although it is unclear why the effects of 3IY were stronger on the control compared to high sugar diet. These results suggest that dopamine levels and/or other interacting genes might differ among wildtype Drosophila strains, in agreement with findings from previous behavioral studies (Colomb and Brembs 2014; Malacrida et al. 2022; Chaudhary et al. 2025). Nevertheless, based on our combined results, we conclude that, while y mutation sensitizes females to low dopamine levels on a high sugar diet (see Fig. 3), more severe dopamine imbalance—caused by CNS dopamine deficiency (Fig. 4) or higher dopamine or 3IY dosage (Fig. 6)—is deleterious to vitellogenic follicles regardless of diet or genetic background. This apparent need for optimal levels of dopamine and/or dopamine signaling for oogenesis is consistent with other studies showing that fine tuning of dopamine levels is important in other contexts and organisms (Yamamoto and Seto 2014; Dobryakova et al. 2015; Zhou et al. 2023).

DISCUSSION

This study expands our understanding of how genetic background can influence responses to high sugar diets, focusing on the previously described ovarian response to a high sugar diet in Drosophila melanogaster (Nunes and Drummond-Barbosa 2023). Importantly, we uncover a role for CNS-derived dopamine in modulating the survival of vitellogenic follicles in Drosophila. Based on our results, we propose the following working model (Fig. 6D): (i) An optimal range of dopamine levels contributes to the survival of vitellogenic follicles on a control diet. (ii) Exposure of wildtype females to a high sugar diet leads to a relatively modest decrease in dopamine levels such that they remain within the optimal range; by contrast, y mutant females are more sensitive to a high sugar diet and dopamine therefore falls below the optimal range, causing increased follicle death. (iii) In wildtype females on either a control or high sugar diet, increased follicle death requires more drastic alterations in dopamine levels induced either by genetic impairment of CNS dopamine production or by high-dose pharmacological manipulations that bring dopamine levels outside of the optimal range (i.e., either very high or very low). Our findings are consistent with observations that chronic consumption of high sugar is associated with decreased dopamine levels in mammals (Rada et al. 2005; Avena et al. 2008; Jacques et al. 2019). The vitellogenic follicle degeneration in Drosophila is also reminiscent of the increased follicle atresia observed in rats on high fat-high sugar diets (de Melo et al. 2021; Rejani et al. 2022; Demirel et al. 2024). Our study therefore raises the question of whether altered dopamine levels interact with diet and genetic background in other organisms, including humans, as a potential source of fertility issues or other chronic illnesses. This question is especially timely considering the prevalence of high sugar consumption in modern societies.

Mechanisms underlying potentially conserved roles of dopamine in oogenesis?

Our findings align with previous research pointing to potential connections between dopamine and female reproduction in a wide range of organisms (Gruntenko and Rauschenbach 2008). For example, earlier studies showed that forcing either very low or very high levels of dopamine in newly eclosed Canton-S flies leads to reduced ovarian size (Neckameyer 1996), and cocaine, which interferes with dopamine signaling (Garris and Wightman 1995), increases vitellogenic follicle death (Sedore Willard et al. 2006). Inhibition of tyrosine hydroxylase in virgin fire ant Solenopsis invicta females lowers egg production (Boulay et al. 2001), while dietary dopamine supplementation was reported to increase ovary activation in queenless Apis mellifera workers (Dombroski et al. 2003). In the bumble bee Bombus ignitus, the brains of newly emerged queens have higher levels of dopamine compared to worker brains, likely driven by nutritional differences (Sasaki et al. 2021). Interestingly, in Drosophila sechellia, which is a specialist fruit fly species adapted solely to the fruit of Morinda citrifolia, specific polymorphisms cause dopamine deficiency and oogenesis arrest unless these flies ingest L-DOPA present in Morinda (Lavista-Llanos et al. 2014). In the zebrafish Danio rerio, dopamine has an inhibitory role in female reproduction by antagonizing induction of pituitary follicle-stimulating hormone and luteinizing hormone by gonadotropin-releasing hormone (Fontaine et al. 2013). Finally, in infertile women with hyperprolactinemia, long-term use of dopaminergic drugs can improve fertility (Crosignani 2012).

Other stresses and inputs besides high sugar also alter dopamine levels during different organismal responses. Dopamine neurons in the brain show strong responses to rewarding and aversive stimuli across organisms (Bromberg-Martin et al. 2010; Rosikon et al. 2023). Stresses including starvation, oxidative stress, and mechanical stress alter tyrosine hydroxylase activity levels in Drosophila, and, conversely, reduction in tyrosine hydroxylase activity alters behavior and locomotive responses to stress (Neckameyer and Weinstein 2005). Mating stimulates dopamine production through expression changes in key dopamine metabolism genes (Burdina et al. 2025). However, much remains unknown regarding the regulation and role of dopamine in the context of female fertility.

Our study opens new questions for future investigation regarding the role of dopamine in modulating Drosophila oogenesis. First, the Drosophila brain contains ~50 morphologically distinct types of dopaminergic neurons organized in multiple clusters that innervate different regions of the brain and have different functions (Hartenstein et al. 2017; Siju et al. 2021; Marquis and Wilson 2022). What neurons serve as the key sources of dopamine in the control of oogenesis and how are they modulated by a high sugar diet? Second, Drosophila insulin-producing neurons have projections that extend outside of the brain to release insulin-like peptides directly into the hemolymph as neurohormones (Rulifson et al. 2002) that controls different processes during oogenesis (LaFever and Drummond-Barbosa 2005). Although dopaminergic neurons typically release dopamine as a neurotransmitter (for signaling to other neurons), there is evidence in flies and mammals suggesting that dopamine may also act as a neurohormone (Goldstein and Holmes 2008; Zhao et al. 2010). Are key dopaminergic neurons signaling to other neurons or releasing dopamine directly into the hemolymph to regulate follicle survival? Third, dopamine can act through different G protein-coupled receptors in two major classes (D1 and D2). Drosophila encodes four dopamine receptors including Dop1R1, Dop1R2, Dop2R, and the non-canonical receptor DopEcR (Siju et al. 2021). What dopamine receptors (and in which neurons/tissues) and downstream molecular, cellular, and physiological mechanisms are required for the effects of dopamine on oogenesis?

Crosstalk between dopamine and serotonin during oogenesis?

In Drosophila and mammals, dopaminergic and serotonergic systems are known to interact with each other during development and in adults (Seo et al. 2008; Yarali et al. 2009; Neckameyer and Bhatt 2012; Niens et al. 2017; Kasture et al. 2018). For example, dopamine levels can affect serotonergic innervation in the brain and gut during Drosophila development (Neckameyer and Bhatt 2012; Niens et al. 2017). Dopamine and serotonin functionally interact in Drosophila and mammals to control different aspects of brain function, including long-term memory formation and behavior, and dopamine–serotonin imbalances are thought to contribute to depression, schizophrenia, and Parkinson’s disease (Seo et al. 2008). Serotonin has also been implicated in the control of oogenesis in the worm Caenorhabditis elegans, frogs, and mammals (Alhajeri et al. 2022; Aprison et al. 2022; Shmukler et al. 2022). The dopamine and serotonin biosynthetic pathways also have biochemical overlaps. Specifically, the DOPA decarboxylase encoded by Ddc, in addition to converting DOPA to dopamine (Fig. 2A), also decarboxylates 5-hydroxytryptophan to serotonin depending on neuronal type (Lundell and Hirsh 1994). Tetrahydrobiopterin is a cofactor for DOPA decarboxylase and for tryptophan phenylalanine hydroxylase (encoded by henna), which catalyzes the conversion of phenylalanine to tyrosine and of tryptophan to 5-hydroxytryptophan depending on substrate availability (Coleman and Neckameyer 2004). In our experiments, DdcDE1 hypomorphic mutants appeared to have elevated levels of vitellogenic follicle death (relative to y1 and other pigmentation mutants; see Fig. 2) on a control diet. Although more severe alterations in dopamine levels in DdcDE1 females might explain this difference, we cannot exclude a possible contribution from altered serotonin levels. Future studies should more directly address whether dopamine functionally interacts with serotonin in the control of oogenesis.

A connection between dietary water, high sugar, and dopamine?

We previously showed that dietary water supplementation can prevent the increased vitellogenic follicle death observed in y* ac* w1118 females on a high sugar diet (Nunes and Drummond-Barbosa 2023). Interestingly, water can stimulate dopamine-producing neurons in both Drosophila and mammals (Lin et al. 2014; Jaksic et al. 2020; Mietlicki-Baase et al. 2021), and a subset of water-responsive neurons in Drosophila has also been shown to respond to sweet stimuli (May et al. 2020). It is tempting to speculate that water might reverse the effects of a high sugar diet on vitellogenic follicles by restoring dopamine homeostasis, although more research will be required to test this possibility.

Yellow: the mystery remains

The y gene family is present across insect species (Ferguson et al. 2011; Gudelly et al. 2024). The y gene is best known for its requirement in the production of melanin from dopamine during cuticle development and there is intense research on its transcriptional and post-transcriptional regulation, especially in the context of the evolution of insect pigmentation (Wittkopp and Beldade 2009; Gudelly et al. 2024). The Yellow protein contains a Major Royal Jelly domain of unknown function and lacks enzymatic activity (Han et al. 2002; Claycomb et al. 2004; Drapeau et al. 2006; Ferguson et al. 2011). Although Yellow has been proposed to function as a structural scaffold (for pigment deposits or pigmentation enzymes) (Hinaux et al. 2018) or as a hormone (Drapeau 2003), its molecular function remains unknown. In this study we find a new connection between y function, sensitivity to dopamine imbalance in females on a high sugar diet, and follicle survival during Drosophila oogenesis, further highlighting the need to understand the molecular connection between Yellow and dopamine-related metabolism. Intriguingly, purified recombinant Yellow proteins from the sand fly Lutzomyia longipalpis bind with relatively high affinity to dopamine and serotonin (Xu et al. 2011), adding a potential role in modulating the availability and/or stability of dopamine to the range of possibilities for how Yellow may act at the molecular level. Our finding that y is important for the high sugar-induced death of early germline cysts independently of dopamine further supports the idea that Yellow might have diverse molecular interactions.

Supplementary Material

Supplementary data file
Supplementary material

ACKNOWLEDGMENTS

The authors would like to thank the Developmental Studies Hybridoma Bank for antibodies, and Jay Hirsh (University of Virginia) and the BDSC (National Institutes of Health P400D018537) for Drosophila stocks. The authors would also like to thank Mallory Spencer, Emily Wessel, Ana Gandara, and Alicia Williams for their careful reading of the manuscript and helpful editing suggestions.

FUNDING

This work was supported by National Institutes of Health (NIH) grant R35 GM140857 (D.D.-B.).

Footnotes

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

DATA AVAILABILITY

Most Drosophila strains used in this study were obtained from the Bloomington Drosophila Stock Center (BDSC). Strains w*;ple2 P{ple+t20}attP2 and w*;ple2 P{pleFS}attP2 were a gift from Jay Hirsch but are now available from BDSC. No new strains were generated in this study. The authors affirm that all data necessary for confirming the conclusions of the article are present within the article, figures, and tables.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary data file
NIHMS2122626-supplement-Supplementary_data_file.xlsx (140.2KB, xlsx)
Supplementary material
NIHMS2122626-supplement-Supplementary_material.pdf (1.4MB, pdf)

Data Availability Statement

Most Drosophila strains used in this study were obtained from the Bloomington Drosophila Stock Center (BDSC). Strains w*;ple2 P{ple+t20}attP2 and w*;ple2 P{pleFS}attP2 were a gift from Jay Hirsch but are now available from BDSC. No new strains were generated in this study. The authors affirm that all data necessary for confirming the conclusions of the article are present within the article, figures, and tables.

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