Biology subjects

Starr, D.

Publications and source records attributed to Starr, D..

4 recordsLinked to original sources

bioRxiv2026

Nuclear envelope-dependent heterochromatin positioning gates the timing of nucleolar assembly in the early embryo

The nucleolus is the largest nuclear condensate, yet how its assembly is developmentally timed remains poorly understood. In the Caenorhabditis elegans embryo, nucleoli normally appear at the 6- to 8-cell stage. Here we show that the LINC complex and nuclear lamina restrain premature nucleolar assembly through heterochromatin organization. Depletion of the embryonic LINC complex proteins SUN-1 or ZYG-12 induces precocious FIB-1-positive nucleoli at the 4-cell stage, particularly in the EMS and P2 blastomeres. LMN-1 depletion produces a more severe phenotype combining premature assembly with impaired disassembly. Loss of the heterochromatin anchor CEC-4 alone has modest effects but strongly suppresses precocious nucleolar assembly caused by LINC complex depletion. LINC complex and lamin perturbations alter the heterogeneity of HPL-2-marked chromatin, and FIB-1 condensates occupy locally HPL-2-depleted regions. These findings identify nuclear envelope-dependent heterochromatin organization as a developmental gate for nucleolar condensate assembly.

cell biology↗

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↗

bioRxiv2024

Active Microtubule-Actin Crosstalk Mediated by a Nesprin-2G-Kinesin Complex

Nesprins are integral membrane proteins that physically couple the nucleus and cytoskeleton. Nesprin-2 Giant (N2G) stands out for its extensive cytoplasmic domain, which contains tandem N-terminal actin-binding calponin-homology domains followed by >50 spectrin repeats and a C-terminal outer nuclear membrane-spanning KASH domain. N2Gs KASH domain interacts with the inner nuclear membrane, lamina-binding SUN proteins within the perinuclear space, forming a linker of nucleoskeleton and cytoskeleton (LINC) complex. Additionally, N2G contains a conserved W-acidic LEWD motif that enables the direct interaction with kinesin-1s light chain, indicating N2Gs involvement with both actin and microtubules. The absence of N2G leads to embryonic lethality in mice, while cellular assays highlight N2Gs role in nuclear positioning across diverse biological contexts. However, the precise mechanisms underlying N2G-mediated nucleocytoskeletal coupling remain unclear. Here we study N2Gs interactions with F-actin and kinesin-1, revealing its functions as an F-actin bundler, a kinesin-1-activating adapter, and a mediator of active cytoskeletal crosstalk. Along with MAP7 proteins, N2G directly links active kinesin-1 motors to F-actin, facilitating actin transport along microtubule tracks. These findings shed light on N2Gs dynamic role as a crosslinker between actin and microtubule cytoskeletons, offering insights into nuclear movement, a fundamental cellular process.

biophysics↗

bioRxiv2020

The Nesprin-1/-2 ortholog ANC-1 regulates organelle positioning in C. elegans without its KASH or actin-binding domains

KASH proteins in the outer nuclear membrane comprise the cytoplasmic half of LINC complexes that connect nuclei to the cytoskeleton. Caenorhabditis elegans ANC-1, an ortholog of Nesprin-1/2, contains actin-binding and KASH domains at opposite ends of a long spectrin-like region. Deletion of either the KASH or calponin homology (CH) domains does not completely disrupt nuclear positioning, suggesting neither KASH nor CH domains are essential. Deletions in the spectrin-like region of ANC-1 led to significant defects, but only recapitulated the null phenotype in combination with mutations in the trans-membrane span. In anc-1 mutants, the ER was unanchored, moving throughout the cytoplasm, and often fragmented. The data presented here support a cytoplasmic integrity model where ANC-1 localizes to the ER membrane and extends into the cytoplasm to position nuclei, ER, mitochondria, and likely other organelles in place.

cell biology↗