Biology subjects

Gregory, E. F.

Publications and source records attributed to Gregory, E. F..

4 recordsLinked to original sources

bioRxiv2025

Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis controlling cytoplasmic macromolecular crowding

Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defects in nuclear mechanics and transcription regulation. Yet these models do not fully explain the complexity of EDMD or other laminopathies. Here, we uncover an emerging pathway linking nuclear lamina defects to the reorganization of cytoplasmic biophysics, revealing how nuclear dysfunction cascades throughout the cell. Using Caenorhabditis elegans EDMD models, we demonstrate that lamin mutations dramatically alter cytoplasmic organization, reducing macromolecular crowding and increasing diffusivity of 40 nm Genetically Encoded Multimeric (GEM) nanoparticles. These striking biophysical changes coincide with nuclear positioning defects and collapsed endoplasmic reticulum architecture, mirroring phenotypes associated with ribosome depletion. We propose a mechanism where mutations in the C. elegans lamin lmn-1 disrupt nucleolar density and ribosome biogenesis, creating a nucleolar-ribosomal axis that propagates defects from the nucleus to the cytoplasm. Genetic interactions between lmn-1 and ribosomes support this regulatory relationship. While individual depletion of other nuclear envelope proteins produces minimal effects, combined loss of the functionally redundant emerin ortholog emr-1 and LEM-domain protein lem-2 phenocopied lmn-1 mutants, demonstrating that cytoplasmic biophysical disruption lies at EDMDs pathogenic core. Our findings establish a paradigm where nuclear lamina defects fundamentally rewire cellular biophysics through nucleolar-ribosomal dysfunction, opening transformative therapeutic avenues for treating laminopathies.

cell biology↗

bioRxiv2025

The KASH protein UNC-83 differentially regulates kinesin-1 activity to control developmental stage-specific nuclear migration

Nuclear migration plays a fundamental role in development, requiring precise spatiotemporal control of bidirectional movement through dynein and kinesin motors. Here, we uncover a mechanism for developmental regulation of nuclear migration directionality. The nuclear envelope KASH protein UNC-83 in Caenorhabditis elegans exists in multiple isoforms that differentially control motor activity. The shorter UNC-83c isoform promotes kinesin-1-dependent nuclear movement in embryonic hyp7 precursors, while longer UNC-83a/b isoforms facilitate dynein-mediated nuclear migration in larval P cells. We demonstrate that UNC-83as N-terminal domain functions as a kinesin-1 inhibitory module by directly binding kinesin heavy chain (UNC-116). This isoform-specific inhibition, combined with differential affinity for kinesin light chain (KLC-2), establishes a molecular switch for directional control. Together, these interdisciplinary studies reveal how alternative isoforms of cargo adaptors can generate developmental stage-specific regulation of motor activity during development.

cell biology↗

bioRxiv2024

Anchorage of H3K9-methylated heterochromatin to the nuclear periphery helps mediate P-cell nuclear migration though constricted spaces in Caenorhabditis elegans

Nuclei adjust their deformability while migrating through constrictions to enable structural changes and maintain nuclear integrity. The effect of heterochromatin anchored at the nucleoplasmic face of the inner nuclear membrane on nuclear morphology and deformability during in vivo nuclear migration through constricted spaces remains unclear. Here, we show that abolishing peripheral heterochromatin anchorage by eliminating CEC-4, a chromodomain protein that tethers H3K9-methylated chromatin to the nuclear periphery, disrupts constrained P-cell nuclear migration in Caenorhabditis elegans larvae in the absence of the established LINC complex-dependent pathway. CEC-4 acts in parallel to an actin and CDC-42-based pathway. We also demonstrate the necessity for the chromatin methyltransferases MET-2 and JMJD-1.2 during P-cell nuclear migration in the absence of functional LINC complexes. We conclude that H3K9-nethylated chromatin needs to be anchored to the nucleoplasmic face of the inner nuclear membrane to help facilitate nuclear migration through constricted spaces in vivo.

genetics↗

bioRxiv2023

Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development. Author summaryMuscular dystrophy is a progressive muscle-wasting disorder that eventually leads to cardiac disease. Mutations in the LMNA gene, which encodes an intermediate filament protein involved in the structure and organization of the nucleus, is a common but poorly understood cause of this disease. How variants across the breadth of LMNA contribute to mechanistic cellular defects that lead to disease is poorly understood, leading to hurdles in diagnosing disease and developing treatments. We found that by introducing amino acid substitutions found in patients with striated muscle disorders caused by LMNA into the conserved lmn-1 gene of the nematode C. elegans, we could rapidly test the function of these variants to better understand their roles. We found that variants modeling diseases that involve both skeletal and cardiac muscle in humans were the most pathogenic in C. elegans, typically affecting both viability and movement, while those that modeled cardiac disease alone had less deleterious effects in C. elegans. Furthermore, we uncovered molecular mechanisms for how lamins interact with other nuclear envelope proteins to carry out their cellular functions. Thus, our new C. elegans models can be used to diagnose and predict the severity of new variants of human LMNA as well as better understanding the molecular mechanisms of lamins in normal development.

cell biology↗