Biology subjects

Moberg, K.

Publications and source records attributed to Moberg, K..

7 recordsLinked to original sources

bioRxiv2026

Sex-specific metabolic regulation by the Drosophila RNA-binding protein Nab2

Conserved RNA binding proteins (RBPs) regulate key steps of gene expression including mRNA processing, export, localization, stability and translation. Human ZC3H14 is a conserved RBP that regulates pre-mRNA processing in neurons and loss of ZC3H14 leads to neurological defects. Studies of Nab2, the Drosophila orthologue of ZC3H14, have identified potential target RNAs involved in metabolism, suggesting Nab2 may influence neurometabolic circuitry. Here, we show a female-specific increase in dilp2 and dilp5 mRNA levels. The dilps encode insulin-like peptides that signal from the brain insulin producing cells (IPCs) to peripheral tissues. Nab2null females have enlarged lipid droplets in the fat body, a tissue analogous to human adipose tissue and liver. Notably, neuronal depletion of Nab2 increases lipid droplet size while neuronal expression of Nab2 in Nab2null female rescues this phenotype supporting a role for Nab2 in a neuronal circuit that regulates dilp levels. Furthermore, depletion of dilp2 or dilp5 from IPCs rescues the enlarged lipid droplet phenotype in Nab2null females indicating that elevated dilp2/dilp5 contributes to enlarged lipid droplets. Together, these data support a female-specific role for Nab2 in brain neurons to support insulin signaling and fat storage, expanding the known functions of RBPs linking neuronal function and metabolic homeostasis.

cell biology↗

bioRxiv2024

The RNA binding protein Nab2 regulates splicing of the RhoGEF trio transcript to govern axon and dendrite morphology

The Drosophila RNA binding protein (RBP) Nab2 acts in neurons to regulate neurodevelopment and is orthologous to the human intellectual disability-linked RBP, ZC3H14. Nab2 governs axon projection in mushroom body neurons and limits dendritic arborization of class IV sensory neurons in part by regulating splicing events in ~150 mRNAs. Analysis of the Sex-lethal (Sxl) mRNA revealed that Nab2 promotes an exon-skipping event and regulates m6A methylation on Sxl pre-mRNA by the Mettl3 methyltransferase. Mettl3 heterozygosity broadly rescues Nab2null phenotypes implying that Nab2 acts through similar mechanisms on other RNAs, including unidentified targets involved in neurodevelopment. Here, we show that Nab2 and Mettl3 regulate the removal of a 5UTR intron in the trio pre-mRNA. Trio utilizes two GEF domains to balance Rac and RhoGTPase activity. Intriguingly, an isoform of Trio containing only the RhoGEF domain, GEF2, is depleted in Nab2null nervous tissue. Expression of Trio-GEF2 rescues projection defects in Nab2nullaxons and dendrites, while the GEF1 Rac1-regulatory domain exacerbates these defects, suggesting Nab2-mediated regulation Trio-GEF activities. Collectively, these data identify Nab2-regulated splicing as a key step in balancing Trio GEF1 and GEF2 activity and show that Nab2, Mettl3, and Trio function in a common pathway that shapes axon and dendrite morphology. Significance StatementO_LIDrosophila Nab2, ortholog of the human RBP ZC3H14 mutated in inherited intellectual disability, acts through unknown RNA targets to control axon and dendrite morphology. C_LIO_LIThis study shows that Nab2 and the Mettl3 methyltransferase guide splicing of trio mRNA, which encodes a conserved GEF-domain protein. Intron retention in trio mRNA leads to an imbalance in levels of two Trio GEF domains in Nab2-deficient neurons and restoring this balance rescues neuronal defects. C_LIO_LIThe authors conclude that Nab2 control of trio splicing is required to pattern axon and dendrite growth and suggests that ZC3H14 may play a similar role in the vertebrate brain. C_LI

molecular biology↗

bioRxiv2024

The Drosophila EcR-Hippo component Taiman promotes epithelial cell fitness by control of the Dally-like glypican and Wg gradient

Rapidly dividing cells can eliminate slow growing neighbors through the apoptotic process of cell competition. This process ensures that only high fitness cells populate embryonic tissues and is proposed to underlie the ability of oncogene-transformed cells to progressively replace normal cells within a tissue. Patches of cells in the Drosophila wing disc overexpressing the oncogenic Taiman (Tai) transcriptional coactivator kill normal neighbors by secreting Spz ligands that trigger pro-apoptotic Toll signaling in receiving cells. However, extracellular signaling mechanisms responsible for elimination of slow growing cells by normal neighbors remain poorly defined. Here we show that slow growing cells with reduced Tai (Tailow) are killed by normal neighbors through a mechanism involving competition for the Wingless (Wg/Wnt) ligand. Elevated Wg signaling significantly rescues elimination of Tailow cells in multiple organs, suggesting that Tai may normally promote Wg activity. Examining distribution of Wg components reveals that Tai promotes extracellular spread of the Wg ligand from source cells across the wing disc, thus ensuring patterned expression of multiple Wg-regulated target genes. Tai controls Wg spread indirectly through the extracellular glypican Dally-like protein (Dlp), which binds Wg and promotes its extracellular diffusion and capture by receptors. Data indicate that Tai likely controls Dlp at two levels: transcription of dlp mRNA and Dlp intracellular trafficking. Overall, these data indicate that the Tai acts through Dlp to enable Wg transport and signaling, and that cell competition in the Tailow model arises due to inequity in the ability of epithelial cells to sequester limiting amounts of the Wg growth factor.

developmental biology↗

bioRxiv2024

Sexual Dimorphism in Age-Dependent Neurodegeneration After Mild Head Trauma in Drosophila: Unveiling the Adverse Impact of Female Reproduction

Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Increasing age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify Sex Peptide (SP) signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights a reduction in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration.

neuroscience↗

bioRxiv2024

Local ecdysone synthesis in a wounded epithelium sustains developmental delay and promotes regeneration in Drosophila

Regenerative ability often declines as animals mature past embryonic and juvenile stages, suggesting that regeneration requires redirection of growth pathways that promote developmental growth. Intriguingly, the Drosophila larval epithelia require the hormone ecdysone (Ec) for growth but require a drop in circulating Ec levels to regenerate. Examining Ec dynamics more closely, we find that transcriptional activity of the Ec-receptor (EcR) drops in uninjured regions of wing discs, but simultaneously rises in cells around the injury-induced blastema. In parallel, blastema depletion of genes encoding Ec biosynthesis enzymes blocks EcR activity and impairs regeneration but has no effect on uninjured wings. We find that local Ec/EcR signaling is required for injury-induced pupariation delay following injury and that key regeneration regulators upd3 and Ets21c respond to Ec levels. Collectively, these data indicate that injury induces a local source of Ec within the wing blastema that sustains a transcriptional signature necessary for developmental delay and tissue repair.

developmental biology↗

bioRxiv2022

An EcR probe reveals mechanisms of the ecdysone-mediated switch from repression-to-activation on target genes in the larval wing disc

Fluctuating levels of steroid hormones provide both systemic and local cues to synchronize metazoan development and control germline and homeostatic processes. The main steroid hormone in Drosophila is ecdysone (Ec), which upon binding of its active form (20E) converts its receptor, EcR, from a transcriptional repressor to activator. Multiple co-repressors and co-activators are proposed to act with EcR in different tissues to control diverse targets and processes, including apoptosis, cell migration, and proliferation. Despite these diverse roles, relatively little is known regarding how EcR translates Ec temporal gradients into modulation of individual target genes. Here we use an Ec-binding fragment of EcR (EcRLBD) as a sponge to sequester coregulators and probe the state of EcR activity as larval wing cells traverse the 3rd instar Ec gradient. This approach reveals a dramatic and rapid shift from EcR mediated repression-to-activation in late L3 cells, and that the extent of repression varies between targets. An Ala483Thr mutation that disrupts binding of the co-repressor Smr compromises the ability of EcRLBD to derepress reporters, but also limits its ability to block activation, suggesting either that a coactivator shares an EcR-interaction interface with Smr or that Smr-repression primes targets for 20E activation. Molecular and genetic data reveal that EcRLBD sequesters 20E, and that EcRLBD phenotypes can be modulated by manipulating intracellular 20E levels with Ec importer (EcI) and Cyp18a1, which inactivates 20E. Finally, we provide evidence that Smr repression of EcR activity varies spatially and by target in the wing disc. In sum these data reveal that relief of EcR-Smr repression is a major contributor to 20E induction of EcR targets in larval wing discs and highlight EcRLBD as an effective probe to define EcR-20E gene regulatory mechanisms in vivo.

developmental biology↗

bioRxiv2019

A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway in Drosophila melanogaster

Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental pathways regulated by Nab2 remain poorly defined. Structural defects in Nab2 null brains resemble defects observed upon disruption of the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, which is also a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP loss-of-function alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR-Nab2) and subsequently for modification of Nab2 null phenotypes. Multiple PCP alleles dominantly modify GMR-Nab2 eye roughening and a subset of these alleles also rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Moreover, alleles of two X-linked PCP factors, dishevelled (dsh) and {beta} amyloid protein precursor-like (Appl), rescue GMR-Nab2 eye roughening in male progeny derived from hemizygous dsh or Appl mutant fathers, suggesting an additional effect inherited through the male germline. These findings demonstrate a consistent pattern of Nab2-PCP genetic interactions that suggest molecular links between Nab2 and the PCP pathway in the developing eye, wing and germline.

developmental biology↗