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Mosquitoes lose their drive to host-seek after a blood meal, yet the molecular and neuronal mechanisms underlying this change remain poorly understood.  In a previous study, Duval et al. (2019) identified the Neuropeptide Y Receptor (NPY) as a potential mediator of this effect.  In the manuscript by Greppi et al, the authors show that NPY-like receptor 7 NPYLR7 acts in specialized rectal cells that sense nutritional cues and relay signals to the nervous system to control reproduction in Aedes aegypti mosquitoes. This work is particularly interesting because it uncovers a completely unexpected neuroendocrine role for the hindgut—a tissue traditionally viewed as a purely osmoregulatory organ—and demonstrates that it is a key site where nutrient sensing is coupled to reproductive investment. This preprint stands out in the field because gut–brain signaling in insects has largely centered on the midgut and central nervous system; the authors reveal a new signaling hub that broadens our understanding of how blood-feeding mosquitoes coordinate physiology and behavior. Their integration of genetics, physiology, imaging, transcriptomics, and ultrastructure provides a strong multi-level support, making the central conclusion—that NPYLR7-expressing rectal pad cells function as a nutrient-sensing node influencing fecundity—highly convincing and influential for future work.

Major comments

1.      Clarification of Genotype-Related Behavioral Differences:

The manuscript would benefit from additional clarification regarding a few observations that could strengthen the interpretation of the phenotypes. In several assays, the heterozygous controls show behavioral outcomes that differ from the wild type (e.g., Figure 3b, day 3; Figure 3d, 60 min and 360 min). It would be helpful if the authors could briefly comment on these differences and whether they might reflect dosage effects, compensatory mechanisms, or assay-specific sensitivity.

Similarly, the wide range of egg viability observed in the npylr7^QF2/QF2 mutants (0–75%, Figure 2c) is intriguing and may provide additional insight into the role of NPYLR7 in reproductive physiology. A brief discussion of potential sources of this variability—for example, differences in the degree of functional disruption among individuals or in physiological states—would greatly aid readers.

To further support interpretation, the authors may also consider adding a brief clarification in the Methods section regarding how npylr7^QF2/+ heterozygotes were distinguished from npylr7^QF2/QF2 homozygotes. This additional detail would help readers fully understand the genotype assignments and clarify any potential confusion.

2.      Clarification of the Mechanistic Link Between NPYLR7 Signaling and Protein Provisioning:

The authors could further explain the concept of “protein provisioning” and how they propose that NPYLR7 contributes to this process. As written, it appears that the authors envision a multifaceted and potentially indirect mechanism in which NPYLR7 activation—perhaps following a blood meal—elicits neuromodulatory signaling from the rectal pads. However, the connection between this signaling and the outcome of protein provisioning remains somewhat unclear. The authors could expand their discussion of the underlying model, detailing how they believe NPYLR7 influences protein provisioning, either directly or indirectly. Strengthening this section would help readers better understand the proposed physiological pathway and its implications.

Minor comments

1.      Males possess only four rectal pads; it would be informative for the authors to briefly discuss whether NPYLR7 might have sex-specific roles and whether the mutants exhibit noticeable changes in male fertility or mating behavior. Even a brief note indicating whether these aspects were examined—or why they may fall outside the current scope—would provide helpful context for readers.

2.      The EM data are visually striking and add substantial depth to the manuscript. The appearance of multilamellar bodies in the mutants is particularly intriguing and suggests important underlying biology. To further strengthen the interpretation, the authors might consider including some quantitative measures—such as vesicle number, area, or subcellular localization—which would not only support the current conclusions but also provide a valuable reference for future comparative studies. In addition, clarifying whether these multilamellar structures are more consistent with cellular stress, defects in vesicle formation, or with autophagic processes would help readers better understand the possible mechanistic implications. Even a brief discussion of alternative causes other than stress would enhance the impact of this compelling dataset.

3.      Since diluting the nutrient content of the blood meal did not fully recapitulate the npylr7 phenotype, it may be helpful to explore whether an artificial meal such as SkitoSnack—designed to closely mimic blood composition—produces similar outcomes. Incorporating or briefly discussing this possibility could further strengthen the authors’ interpretation and provide a useful direction for future studies aimed at dissecting the nutritional components underlying the phenotype.

4.      The transcriptomic analysis provides valuable insight into hindgut gene expression. Because the dataset includes both ileum and rectum, the authors might briefly acknowledge that pooling these tissues could potentially dilute rectal pad–specific signatures. A short discussion of this limitation would help readers interpret the data more accurately and appreciate the complexity of identifying region-specific transcriptional changes.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they did not use generative AI to come up with new ideas for their review.