Biology subjects

Been, M.

Publications and source records attributed to Been, M..

5 recordsLinked to original sources

bioRxiv2026

Polyamine dysregulation converges with RASopathies on RAS/MAPK and sensory processing phenotypes in Drosophila

RASopathies are developmental conditions associated with cognitive and sensory processing impairments. They are caused by pathogenic variants in genes that result in overactivation of the RAS/MAPK signaling pathway. Genes linked to this pathway have been reported to be enriched among Drosophila models with habituation deficits, a behavioral phenotype reflecting sensory filtering. To identify hidden RASopathies - monogenic disorders that converge on RAS/MAPK overactivation without being classically linked to the pathway - we generated 89 and screened 41 viable habituation-deficient Drosophila RNAi models for RAS/MAPK overactivation, measured as an increased phosphorylated ERK to ERK ratio. This screen identified Sms, the ortholog of human spermine synthase (SMS), implicated in Snyder-Robinson syndrome. RAS/MAPK overactivation along with hyperreactivity and habituation impairments are confirmed in a full loss-of-function mutant. A RNAi screen targeting polyamine pathway genes identified Sat (human SAT1/2, SATL1) to reproduce these phenotypes. Knockdown of Sms or Sat in GABAergic neurons impaired habituation, implicating polyamine metabolism in inhibitory circuit function. These findings reveal previously unrecognized convergence between polyamine dysregulation and RASopathies, suggesting shared therapeutic opportunities through modulation of either pathway. SUMMARY STATEMENTUsing Drosophila, we uncovered polyamine metabolism genes, Sms and Sat, as modulators of RAS/MAPK and sensory processing, revealing a shared mechanism between polyaminopathies and RASopathies that may inform unified therapies.

genetics↗

bioRxiv2025

Excessive activation of the RAS/MAPK pathway triggers adult-onset motor axonal degeneration

Axonal and synaptic degeneration are key hallmarks of neurodegenerative diseases, but the underlying molecular mechanisms are incompletely understood. Here, we performed an unbiased forward genetic mosaic screen to identify genes required for maintenance of adult motor axons and neuromuscular junctions (NMJs) in the Drosophila leg. We identified 49 mutations in 30 genes, including mutations in 8 genes resulting in adult-onset progressive degeneration. We found that loss of pebbled (peb) function results in adult-onset motor axonal and NMJ degeneration, and age-dependent motor deficits. Peb is the Drosophila RREB1 ortholog, a C2H2 zinc-finger transcription factor that negatively regulates transcription of RAS/MAPK pathway target genes. Loss of peb function resulted in excessive RAS/MAPK pathway activation, and loss of function of other negative regulators of the RAS/MAPK pathway also induced adult-onset progressive NMJ degeneration and motor deficits. Importantly, treatment of adult flies with the MEK1/2 inhibitor mirdametinib induced a dosage-dependent rescue of peb mutant motor neurodegenerative phenotypes. Thus, RAS/MAPK pathway overactivation results in adult-onset progressive neurodegeneration, which can be prevented by RAS/MAPK pathway inhibition.

neuroscience↗

bioRxiv2024

FUS controls muscle differentiation and structure through LLPS mediated recruitment of MEF2 and ETV5

FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.

neuroscience↗

bioRxiv2021

TORC1 and PKA activity towards ribosome biogenesis oscillates in synchrony with the budding yeast cell cycle

Recent studies have revealed that the growth rate of budding yeast and mammalian cells varies during the cell cycle. By linking a multitude of signals to cell growth, the highly conserved Target of Rapamycin Complex 1 (TORC1) and Protein Kinase A (PKA) pathways are prime candidates for mediating the dynamic coupling between growth and division. However, measurements of TORC1 and PKA activity during the cell cycle are still lacking. Following the localization dynamics of two TORC1 and PKA targets via time-lapse microscopy in hundreds of yeast cells, we found that the activity of these pathways towards ribosome biogenesis fluctuates in synchrony with the cell cycle even under constant external conditions. Mutations of upstream TORC1 and PKA regulators suggested that internal metabolic signals partially mediate these activity changes. Our study reveals a new aspect of TORC1 and PKA signaling, which will be important for understanding growth regulation during the cell cycle.

systems biology↗

bioRxiv2020

The Drosophila FUS ortholog cabeza promotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

The number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection. Author SummarySkeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit fly Drosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of the Drosophila caz gene results in muscle developmental defects. Loss of caz function in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss of caz function leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.

developmental biology↗