Biology subjects

Weaver, L. N.

Publications and source records attributed to Weaver, L. N..

9 recordsLinked to original sources

bioRxiv2026

Genomic Profiling of Estrogen-Related Receptor Identifies Adult Adipocyte-Specific Targets in Drosophila

Adipose tissue is a key metabolic organ for carbohydrate and lipid metabolism. Multiple nutrient sensing pathways and metabolic enzymes operate in adipocytes to control energy production and lipid mobilization in response to physiological conditions. Important regulators of glycolytic and lipid metabolism in many species are members of the estrogen-related receptor (ERR) family of nuclear receptors. We previously showed that ERR is required for transcriptional regulation of glycolytic and pentose phosphate pathway enzymes in adult Drosophila females, consistent with what is observed in ERR mutant males and larvae. However, the cell-type specific targets of ERR in adipose and other tissues have not been fully elucidated. Here, using a modified targeted DamID approach (NanoDam), we identified ERR occupancy specifically in adult adipocytes at the loci that encode genes involved in glycolysis, the pentose phosphate pathway, and fatty acid metabolism. Overall, our results predict that ERR centrally functions in adipose tissue to regulate multiple metabolic pathways.

physiology↗

bioRxiv2026

RNA Sequencing in Adult Drosophila Females Identifies Estrogen-Related Receptor-Dependent Transcriptional Changes in Metabolism, DNA Replication, and Translation

Nuclear receptors, transcription factors essential for organism growth, development, and reproduction, are expressed in a variety of tissues, with some exhibiting differential expression between males and females. The Estrogen-related receptor (ERR) is a conserved metabolic nuclear receptor required for energy metabolism and lipid accumulation. While previous studies in Drosophila have identified potential ERR targets from mixed sex larval populations and adult males, it is unclear whether transcriptional targets and biological pathways downstream of ERR are altered in a sex-specific manner. Here, we took an RNA sequencing approach to identify candidate ERR targets specifically in adult females and compared differentially expressed genes to a published male-specific dataset. Whole body conditional knockout of ERR significantly downregulated transcription of enzymes associated with glycolysis and the pentose phosphate pathway. In contrast, components of the DNA replication machinery were selectively downregulated in adult females, whereas ribosome biogenesis transcription was increased. Our results have further defined the metabolic targets of ERR between males and females, as well as suggest that ERR regulates DNA replication and global translation in females. SUMMARYIn this manuscript, we used RNA sequencing to identify differential expression of transcripts dependent on the nuclear receptor ERR in Drosophila adult females. We find that ERR is required for activating transcription of glycolytic and pentose phosphate pathway enzymes, as observed in larvae and adult males. Furthermore, compared to males, loss of ERR in females specifically decreased DNA replication enzyme components while upregulating ribosomal components. Our results suggest that nuclear receptors have common and sex-specific targets, which will be of interest for those in the nuclear receptor and sexual dimorphism fields.

physiology↗

bioRxiv2025

Adipocyte-Derived Amino Acid Storage Proteins are Required for Germline Stem Cell Maintenance in Adult Drosophila Females

Tissue homeostasis is dependent on precise coordination between endocrine organs in response to changes in organism physiology. Secreted circulating factors from adipocytes regulate the behavior of stem cell lineages in peripheral tissues in multiple organisms. In addition to their endocrine roles, Drosophila adipocytes store and secrete amino acid storage proteins throughout development. During the larval feeding period, adipocytes secrete storage proteins into the hemolymph, which are reabsorbed by the adipose tissue during metamorphosis to control adult organ size and fertility. Despite the known functions for storage proteins during the larval stages, their requirement during Drosophila adulthood and reproduction are uncharacterized. We discover that adipocyte-specific knockdown of the storage proteins Larval serum protein 1 (Lsp1) /{beta}/{psi} and Larval serum protein 2 (Lsp2) results in a decrease in GSC maintenance. We further reveal that decreased GSC number is due to downregulation of Target of Rapamycin (TOR) signaling in GSCs, suggesting compromised amino acid sensing directly in GSCs. We also find that the proteins that mediate storage protein adipocyte reabsorption, Fat body protein 1 (Fbp1) and Fat body protein 2 (Fbp2), are expressed in ovarian follicle cells. Intriguingly, Fbp1 nor Fbp2 appear to be required in follicle cells for GSC maintenance, suggesting undiscovered requirements for amino acid storage proteins in oogenesis. Our results highlight a novel role for Drosophila amino acid storage proteins during adulthood and in regulating tissue stem cell lineages.

developmental biology↗

bioRxiv2025

Reexamining the evolutionary history of the mammalian medial pterygoid muscle

In non-mammalian synapsids, feeding and hearing are closely linked because some jaw bones are involved in both functions. The evolutionary decoupling of these two systems in early mammals likely catalyzed greater specialization of feeding and hearing. Although fossil osteological changes during this process are well documented, the corresponding evolutionary changes to soft tissue anatomy are less certain. The medial pterygoid muscle is a jaw adductor that is central to this evolutionary transition because in many fossil lineages it inserted near or possibly on jaw bones involved in both feeding and hearing. In therians (placentals and marsupials), the medial pterygoid muscle develops medial to Meckels cartilage and inserts on the mandibular angular process. Similarly, non-mammalian cynodonts are often reconstructed with a medial pterygoid muscle passing medial to the ossified Meckels cartilage, inserting on the dentary angular (i.e., pseudangular) process. Thus, the traditional interpretation is that the medial pterygoid remained medial to Meckels cartilage through the evolutionary transitions from early cynodonts to therians. Here we highlight issues with that interpretation: the medial pterygoid muscle inserts lateral (not medial) to Meckels cartilage in monotremes and, presumably, early mammal groups (e.g., spalacotherioids) that lacked an angular process. This suggests at least two possible explanatory hypotheses: 1) the medial pterygoid muscle is evolutionarily labile, shifting in position relative to Meckels cartilage multiple times or 2) the medial pterygoid muscle did not insert on the pseudangular process of non-mammalian cynodonts and instead inserted on the mandibular medial ridge, dorsal to Meckels cartilage. We advocate for the latter hypothesis, proposed by Patterson (1956), which suggests that the medial pterygoid did not shift medial to Meckels cartilage until the complete separation of the ear and jaw in cladotherians (therians and close relatives), with the shift in position possibly triggering the evolution of the therian angular process as an insertion site. Pattersons hypothesis is in line with a growing body of evidence that indicate concomitant evolutionary changes of muscles, ears, and jaws at the cladotherian node were important catalysts for the evolution of hearing and feeding specializations in extant mammals.

evolutionary biology↗

bioRxiv2025

Locomotor Trends Among Early Mammals Illuminated by Predictors of Arboreality from the Mammalian Appendicular Skeleton

Arboreal locomotion is a common trait among extant mammals, and it likely evolved independently in numerous Mesozoic and Cenozoic mammalian lineages. We review evidence for the evolution of arboreality within lineages of early mammals and their stem relatives (Synapsida) while also emphasizing the uncertainty of locomotor inferences of fossil lineages. An improved understanding of the evolutionary origins and prevalence of arboreality in early mammals requires robust links between morphological traits and locomotor behaviors that can be applied to fossils. To this end, we use a large comparative dataset of linear measurements taken on extant mammalian postcranial specimens to evaluate the skeletal proxies that best differentiate arboreality from other locomotor modes. Consistent with previous research, we find that measures of digit length and elbow proportions are especially powerful predictors of climbing. Locomotor predictions based on single measurements or ratios are improved when phylogeny is incorporated into models. Nonetheless, combining multiple functionally relevant traits into our models yields robust predictions of locomotor mode even without incorporating phylogenetic information--this is especially encouraging for fossil groups with unstable phylogenies. We test these locomotor proxies in three early-mammalian case studies--Multituberculata, Plesiadapiformes, and early Theria. We find that multituberculates had a wide locomotor breadth whereas plesiadapiforms all had a high probability of climbing, consistent with previous studies. However, some Mesozoic therians in our sample are predicted to be ground-dwellers, conflicting with the hypothesis that the ancestral therian was scansorial or arboreal. The predictive tools presented here will improve locomotor inferences for small mammals, further illuminating the prevalence and importance of arboreality in early mammalian evolution.

paleontology↗

bioRxiv2025

Estrogen-Related Receptor is Required in Adult Drosophila Females for Germline Stem Cell Maintenance

Stem cell self-renewal and proper tissue function rely on conserved metabolic regulators to balance energy production with inter-organ metabolic trafficking. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism. In mammals, ERRs have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole Drosophila ERR ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, ERR is required in adult Drosophila males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing of the role of ERR in Drosophila metabolism, whether ERR has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in Drosophila, we used the established adult female germline stem cell (GSC) lineage as a model. We found that whole-body ERR knockout in adult females using conditional heat shock-driven FLP-FRT recombination significantly reduces egg production and decreases GSC number. In addition, we found that ERR activity is required cell-autonomously in the adult female germline for maintenance of GSCs; whereas ERR regulation of GSCs is independent of its activity in adult female adipocytes. Our results highlight an ancient and conserved role for ERRs in the regulation of stem cell self-renewal. SUMMARYTissue function and regeneration are dependent on stem cell populations, which relies on the coordination of energy homeostasis between multiple tissues within an organism. Zike et al report that the estrogen-related receptor (ERR) is required in adult Drosophila females to maintain germline stem cell number in the ovary to promote egg production. Furthermore, ERR regulation of stem cell maintenance is dependent on its cell autonomous role in the germline, but not through adipocyte-specific ERR activity. These findings demonstrate that the sole Drosophila ERR has a conserved role in regulating stem cell lineages (similar as the mammalian ERR{beta} ortholog) and can be used as a model to understand regulation of stem cell lineages as well as metabolism.

developmental biology↗

bioRxiv2023

Auxin Exposure Disrupts Feeding Behavior and Fatty Acid Metabolism in Adult Drosophila

The ease of genetic manipulation in Drosophila melanogaster using the Gal4/UAS system has been beneficial in addressing key biological questions. Current modifications of this methodology to temporally induce transgene expression require temperature changes or exposure to exogenous compounds, both of which have been shown to have detrimental effects on physiological processes. The recently described auxin-inducible gene expression system (AGES) utilizes the plant hormone auxin to induce transgene expression and is proposed to be the least toxic compound for genetic manipulation, with no obvious effects on Drosophila development and survival in one wild-type strain. Here we show that auxin delays larval development in another widely-used fly strain, and that short- and long-term auxin exposure in adult Drosophila induces observable changes in physiology and feeding behavior. We further reveal a dosage response to adult survival upon auxin exposure, and that the recommended auxin concentration for AGES alters feeding activity. Furthermore, auxin fed male and female flies exhibit a significant decrease in triglyceride levels and display altered transcription of fatty acid metabolism genes. Although fatty acid metabolism is disrupted, auxin does not significantly impact adult female fecundity or progeny survival, suggesting AGES may be an ideal methodology for studying limited biological processes. These results emphasize that experiments using temporal binary systems must be carefully designed and controlled to avoid confounding effects and misinterpretation of results.

physiology↗

bioRxiv2022

A cautionary note on quantitative measures of phenotypic convergence

Tests of phenotypic convergence can provide evidence of adaptive evolution, and the popularity of such studies has grown in recent years due to the development of novel, quantitative methods for identifying and measuring convergence. These methods include the commonly applied C1-C4 measures of Stayton (2015), which measure morphological distances between lineages, and Ornstein-Uhlenbeck (OU) evolutionary model-fitting analyses, which test whether lineages convergently evolved toward adaptive peaks. We test the performance of C-measures and other convergence measures under various evolutionary scenarios and reveal a critical issue with C-measures: they often misidentify divergent lineages as convergent. We address this issue by developing novel convergence measures--Ct1-Ct4-measures--that measure distances between lineages at specific points in time, minimizing the possibility of misidentifying divergent taxa as convergent. Ct-measures are most appropriate when focal lineages are of the same or similar geologic ages (e.g., extant taxa), meaning that the lineages evolutionary histories include considerable overlap in time. Beyond C-measures, we find that all convergence measures are influenced by the position of focal taxa in phenotypic space, with morphological outliers often statistically more likely to be measured as strongly convergent by chance. Further, we mimic scenarios in which researchers assess convergence using OU models with a priori regime assignments (e.g., classifying taxa by ecological traits), and we find that multiple-regime OU models with phenotypically divergent lineages assigned to a shared selective regime often outperform simpler models. This highlights that model support for these multiple-regime OU models should not be assumed to always reflect convergence among focal lineages of a shared regime. Our new Ct1-Ct4-measures provide researchers with an improved comparative tool, but we emphasize that all available convergence measures are imperfect, and researchers should recognize the limitations of these methods and use multiple lines of evidence when inferring and measuring convergence.

evolutionary biology↗

bioRxiv2019

RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking

High RanGTP around chromatin is important for governing spindle assembly during meiosis and mitosis by releasing the inhibitory effects of importin /{beta}. Here we examine how the Ran gradient regulates Kinesin-14 function to control spindle organization. We show that Xenopus Kinesin-14, XCTK2, and importin /{beta} form an effector gradient, which is highest at the poles that diminishes toward the chromatin and is inverse of the RanGTP gradient. Importin /{beta} preferentially inhibit XCTK2 anti-parallel microtubule cross-linking and sliding by decreasing the microtubule affinity of the XCTK2 tail domain. This change in microtubule affinity enables RanGTP to target endogenous XCTK2 to the spindle. We propose that these combined actions of the Ran pathway are critical to promote Kinesin-14 parallel microtubule cross-linking at the spindle poles to cluster centrosomes in cancer cells. Furthermore, our work illustrates that RanGTP regulation in the spindle is not simply a switch, but rather generates effector gradients where RanGTP gradually tunes the activities of spindle assembly factors.\n\nSummaryEms-McClung et al. visualize a RanGTP effector gradient of association between XCTK2 and importin /{beta} in the spindle. The importins preferentially inhibit XCTK2-mediate anti-parallel microtubule cross-linking and sliding, which allows XCTK2 to cross-link parallel microtubules and help focus spindle poles.

cell biology↗