Search bioRxiv⌕ Search

bioRxiv · 10.64898/2026.11.03.764014

The role of the fruitless P3 transcript in development in Drosophila melanogaster

Abstract

The generation of multiple transcripts from a single gene through alternative promoter usage and alternative splicing is a major source of functional diversity in eukaryotic genomes. The fruitless (fru) gene of Drosophila melanogaster is a classic example of transcript complexity, producing at least 15 transcript isoforms through the use of alternative promoters and terminal exons. While transcripts derived from the sex-specifically spliced P1 promoter have been extensively studied for their roles in sex determination and courtship behaviour, the functions of most non-sex-specific fru transcripts remain poorly understood. Previous studies suggested that transcripts originating from the P3 and/or P4 promoters may contribute to developmental viability, but their individual roles could not be resolved because available mutations disrupted multiple transcript classes simultaneously. Here, we used transcript-specific RNA interference (RNAi) and the Gal4/UAS system to investigate the function of fru P3 transcripts. Loss of P3 expression significantly increased developmental time to pupariation and resulted in complete lethality during pupal development despite normal survival to pupariation. Most mortality occurred during early and mid-pupal stages, indicating a critical requirement for P3-derived transcripts during metamorphosis. Notably, P3 knockdown did not phenocopy complete loss of fruitless, as knockdown individuals survived substantially later into development than fru null mutants, suggesting that additional fruitless transcript classes contribute essential functions during earlier developmental stages. Together, these findings establish an independent developmental role for the fru P3 transcript class and demonstrate that transcript-specific functions contribute substantially to the biological complexity of the fruitless locus.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kulinski, S. A., Yeung, W., Moehring, A. J.. 2026-11-04. The role of the fruitless P3 transcript in development in Drosophila melanogaster. https://doi.org/10.64898/2026.11.03.764014

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Novel Regulators of Sugar-dependent Food Consumption in Drosophila melanogaster

Diet and genetic background interact to influence food consumption, yet the genetic basis of diet-dependent feeding behavior remains poorly understood. Here, we used genome-wide association analysis (GWAS) to investigate the genetic regulation of sugar-dependent food consumption in Drosophila melanogaster. Food intake was quantified in 176 lines of the Drosophila Genetic Reference Panel (DGRP) using the Con-Ex (Consumption-Excretion) assay on low- and high-sugar foods. Flies showed compensatory feeding, consuming more low-sugar food than high-sugar food, and this behavior was largely maintained across genotypes. Additionally, the magnitude and overall consumption varied several-fold among lines, with broad-sense heritability of 0.53 to 0.66 across sexes and diets. Association analysis across six sex- and diet-specific phenotypes identified 161 variants mapping to 118 candidate genes, which shared almost no loci between dietary conditions, indicating that consumption on the two foods is largely under separate genetic control. RNAi knockdown of candidate genes identified CG42673 and Tmtc2, whose knockdown increased consumption across sexes and diets and was reproduced in independent experiments. Together, these findings show that natural genetic variation contributes substantially to diet-dependent feeding and identify candidate regulators of sugar-based food consumption in Drosophila.

genetics↗

Perturbation-induced gene programs map the hidden regulatory architecture of complex diseases

Steady-state molecular profiles incompletely capture the regulatory programs through which genetic variation influences complex disease, particularly programs that emerge only when cells are perturbed. Here, we introduce Perturbscape, a computational framework that learns multiscale gene programs for individual perturbations in a CRISPR Perturb-seq screen using linear and nonlinear contrastive approaches alongside complementary program-learning methods, and integrates them with human genetics to prioritize disease-relevant genes, perturbations and downstream regulatory pathways. Across 15,859 perturbation-by-context profiles from 7 Perturb-seq systems and 53 complex diseases and traits (mean GWAS N=291K), perturbation-induced programs showed up to 4.3-fold higher heritability informativeness than analogous steady-state multi-tissue gene prioritization, and retained significant conditional heritability informativeness across all 34 matched cell system-trait comparisons after accounting for steady-state prioritization. Preserving perturbation-specific programs further yielded 2.5-5.3-fold higher trait relevance scores than programs derived from control cells, pooled perturbations or differential-expression summaries. In K562, Perturbscape-prioritized genes showed stronger enrichment for rare-variant burden genes than steady-state prioritization and were supported by orthogonal enhancer CRISPRi screens. In HepG2, LDL cholesterol-associated perturbation-induced programs specifically revealed statin-responsive pathways not significantly enriched by steady-state PoPS prioritization, supported by pharmacological transcriptional responses and population plasma proteomics. Perturbscape also recovered blood-related trait-conditioned trans-regulatory relationships that were specifically supported by population trans-eQTLs in IFN-gamma-stimulated monocytes (OR = 1.30, P=1.6e-05). Perturbscape further revealed developmental-stage-specific convergence between monogenic diabetes regulators and polygenic T2D risk during pancreatic islet differentiation, and neuronal-subclass-specific autism-associated regulatory programs in vivo. Together, these findings establish perturbation-induced gene programs as a complementary layer of disease-relevant regulatory information, revealing genetically informative pathways and context-specific regulatory relationships incompletely represented by steady-state molecular atlases.

genetics↗

Deep-intronic variants in USH2A: the importance of model selection in variant interpretation and pathogenicity assessment

Interpreting splice-altering USH2A variants is challenging when these result in the alteration of splicing in only a fraction of transcripts. We investigated two deep-intronic USH2A variants from a single case, the inherited variant c.5573-834A>G and the de novo variant c.11047+345A>G, using a minigene splice assay and transcript analysis in patient-derived photoreceptor precursor cells and nasal epithelial cells. The minigene assay revealed the inclusion of a pseudoexon in the presence of the c.11047+345A>G variant, but did not reproduce previously reported aberrant splicing for c.5573-834A>G. In patient-derived cells, c.5573-834A>G resulted in the inclusion of a pseudoexon in part of the transcripts, whereas c.11047+345A>G did not result in detectable levels of aberrantly spliced transcripts. To assess the impact of residual wildtype transcripts on retinal function, we used the previously developed humanized ush2aPE40+M1 knock-in zebrafish model which allows the modeling of the impact of mixed wildtype and pseudoexon-containing ush2a transcripts. This model demonstrated that detectable levels of usherin expression are maintained even when only a fraction of wildtype transcripts lacking pseudoexon inclusion remain. Collectively, these findings advocate for a more nuanced classification of partially splice-altering USH2A variants. The mere presence of alternative transcripts should not be considered sufficient evidence for pathogenicity. Within this framework, data on the c.5573-834A>G variant do not support a (likely) pathogenic classification, and findings related to the c.11047+345A>G variant are consistent with a likely benign classification.

genetics↗