Transgenic <i>Drosophila</i> Expressing Active Human LH Receptor in the Gonads Exhibit a Decreased Fecundity: Towards a Platform to Identify New Orally Active Modulators of Gonadotropin Receptor Activity

• Main Authors: Amir Mahamid (Author), David Ben-Menahem (Author)
• Format: Book
• Published: MDPI AG, 2024-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Background/Objectives: The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and their receptors are major regulators of reproduction in mammals and are absent in insects. We previously established transgenic <i>Drosophila</i> lines expressing a constitutively active human LH receptor variant (LHR^D578Y) and the wild-type receptor (LHR^wt; inactive in the absence of an agonist). That study showed that ubiquitously expression of LHR^D578Y-but not of LHR^wt-resulted in pupal lethality, and targeted expression in midline cells resulted in thorax/bristles defects. To further study the <i>Drosophila</i> model for an in vivo drug screening platform, we investigated here whether expressing LHR^D578Y in the fly gonads alters reproduction, as shown in a transgenic mice model. Methods: The receptor was expressed in somatic cells of the gonads using the tissue-specific <i>traffic jam</i>-Gal4 driver. Western blot analysis confirmed receptor expression in the ovaries. Results: A fecundity assay indicated that the ectopic expression of LHR^D578Y resulted in a decrease in egg laying compared to control flies carrying, but not expressing the transgene (~40% decrease in two independent fly lines, <i>p</i> < 0.001). No significant reduction in the number of laid eggs was seen in flies expressing the LHR^WT (<10% decrease compared to non-driven flies, <i>p</i> > 0.05). The decreased egg laying demonstrates a phenotype of the active receptor in the fly gonads, the prime target organs of the gonadotropins in mammals. We suggest that this versatile <i>Drosophila</i> model can be used for the pharmacological search for gonadotropin modulators. Conclusions: This is expected to provide: (a) new mimetic drug candidates (receptor-agonists/signaling-activators) for assisted reproduction treatment, (b) blockers for potential fertility regulation, and (c) leads relevant for the purpose of managing extra gonadotropic reported activities.

Item Description

10.3390/ph17101267
1424-8247