Genetic sex of enteric neurons enables ovarian relaxin togate maternal gut plasticity

Silva, B.; Tsakani, E.; De, J.; Kontopoulos, A.; Gaspar, P.; Hiridjee, A.; Rosselli, C.; de Juan-Sanz, J.; Campusano, J. M.; Treiber, C. D.; Waddell, S.; Miguel-Aliaga, I.; Hadjieconomou, D.

doi:10.64898/2026.01.09.698651

bioRxiv · 10.64898/2026.01.09.698651

Genetic sex of enteric neurons enables ovarian relaxin togate maternal gut plasticity

Silva, B.·Tsakani, E.·De, J.·Kontopoulos, A.·Gaspar, P.·Hiridjee, A.·Rosselli, C.·de Juan-Sanz, J.·Campusano, J. M.·Treiber, C. D.·Waddell, S.·Miguel-Aliaga, I.·Hadjieconomou, D.

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Abstract

Animals must align intestinal plasticity and feeding with reproductive state, yet the checkpoint that gates these adaptations is unknown. Here we show that an ovary-to-enteric-neuron axis gates the onset of maternal gut plasticity in Drosophila. Genetic sex establishes endocrine competence in a subset of enteric neurons via the sex determination pathway, enabling female-specific expression of the relaxin-family receptor Lgr3. After mating, steroid signalling increases Lgr3 receptor expression, priming these neurons for reproductive adaptation. Once oocytes mature fully, follicle cells secrete the relaxin-like hormone dILP8, which activates Lgr3 to trigger gut enlargement and increased feeding. Disrupting the sex determination pathway in enteric neurons, Lgr3, or ovarian dILP8 prevents gut enlargement and reduces feeding. Thus, genetic sex establishes competence, steroid signalling primes it, and ovarian relaxin triggers it, defining a maternal intestinal plasticity checkpoint that ensures gut adaptations initiate only once reproduction is underway and energy demands peak. Our findings delineate an ovary-to-enteric-neuron axis that couples reproductive state to maternal gut plasticity.

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Silva, B., Tsakani, E., De, J., Kontopoulos, A., Gaspar, P., Hiridjee, A., Rosselli, C., de Juan-Sanz, J., Campusano, J. M., Treiber, C. D., Waddell, S., Miguel-Aliaga, I., Hadjieconomou, D.. 2026-01-10. Genetic sex of enteric neurons enables ovarian relaxin togate maternal gut plasticity. https://doi.org/10.64898/2026.01.09.698651

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