About

Daniel A. Starr is an Associate Dean of Research and a Professor of Molecular and Cellular Biology at the College of Biological Sciences, UC Davis. His research focuses on the mechanisms of nuclear migration within cells, particularly how nuclei and other organelles are positioned during development. Using the model organism Caenorhabditis elegans, he employs imaging, genetic, biochemical, and molecular approaches to study nuclear positioning, a process critical for proper development and linked to diseases such as Lisencephaly and Muscular Dystrophy. Starr's work aims to elucidate the basic biological mechanisms underlying nuclear migration and anchoring, contributing to a deeper understanding of cell biology and developmental processes.

Research topics

• Biology
• Cell biology
• Genetics
• Molecular biology
• Biophysics

Selected publications

• Active microtubule-actin cross-talk mediated by a nesprin-2G–kinesin complex

  Science Advances · 2025-02-21 · 16 citations

  articleOpen access

  Nesprin-2 Giant (N2G) is a large integral membrane protein that physically connects the nucleus to the cytoskeleton, but how N2G performs this activity to maintain nuclear positioning and drive nuclear movement is unclear. This study investigates N2G's role in nucleocytoskeletal coupling, a process critical for cellular function and development. We uncover multiple roles for N2G, including its activity as an F-actin bundler, an adapter that activates kinesin-1 motors, and a mediator of cytoskeletal cross-talk. Notably, N2G directly links kinesin-1 to F-actin, enabling the transport of actin filaments along microtubule tracks, establishing active cross-talk between the actin and microtubule cytoskeletons. These findings provide crucial insights into nuclear movement, advancing our understanding of fundamental cellular processes and their implications in development and disease.

  PublisherDOI

• KASH proteins transform from passive tethers to dynamic conductors of motor-driven nuclear dynamics

  Current Opinion in Cell Biology · 2025-08-10

  reviewOpen access

  Nuclear-cytoskeletal coupling orchestrates critical cellular processes from migration to tissue organization. At the core of this machinery, outer nuclear membrane Klarsicht/ANC-1/SYNE homology (KASH) proteins function as sophisticated molecular conductors rather than simple structural tethers. This review examines three principles redefining these versatile proteins: specialized interfaces for selective microtubule motor protein recruitment that orchestrate diverse chromosomal and nuclear dynamics, coordination of multiple cytoskeletal systems through simultaneous engagement with actin and microtubules, and tissue-specific regulation that explains the diverse KASH protein-related disease manifestations. This framework provides insights into conditions from muscular dystrophy to neurodegeneration and suggests targeted therapeutic opportunities.

  PublisherDOI

• Nuclear deformability depends on H3K9-methylated heterochromatin anchorage to the nuclear periphery in <i>Caenorhabditis elegans</i>

  Genetics · 2025-05-07 · 2 citations

  articleOpen accessSenior author

  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 linker of nucleoskeleton and cytoskeleton (LINC) complex-dependent pathway. This effect was suppressed by mutations that stabilize the lamin LMN-1. CEC-4 acts in parallel to an actin and CDC-42-based pathway. We also demonstrate the necessity for the chromatin methyltransferase MET-2 and the demethylase JMJD-1.2 during P-cell nuclear migration in the absence of functional LINC complexes. We conclude that H3K9-methylated chromatin needs to be anchored to the nucleoplasmic face of the inner nuclear membrane to help facilitate nuclear migration through constricted spaces in vivo.

  PublisherOA PDFDOI

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

  Current Biology · 2025-09-08 · 1 citations

  articleOpen accessSenior author

  Nuclear migration plays a fundamental role in development, requiring precise spatiotemporal control of bidirectional movement through dynein and kinesin motors. Here, we uncover a differential isoform-dependent mechanism for developmental regulation of nuclear migration directionality. The nuclear envelope Klarsicht/ANC-1/Syne homology (KASH) protein UNC-83 in Caenorhabditis elegans exists in multiple isoforms that differentially control motor activity to achieve tissue-specific nuclear positioning. 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 the UNC-83a-specific N-terminal domain functions as a kinesin-1 inhibitory module by directly binding the kinesin heavy chain (UNC-116). This interaction prevents kinesin-1 activation and reduces the protein's affinity for kinesin light chain (KLC-2), allowing for dynein-mediated transport. By contrast, UNC-83c exhibits high-affinity binding to KLC-2, promoting kinesin-1 activation for plus-end-directed movement. AlphaFold structural predictions reveal that UNC-83 contains five spectrin-like repeats, with two located within the inhibitory N-terminal domain. Genetic analysis demonstrates that these spectrin-like repeats are essential for dynein-dependent P cell nuclear migration but dispensable for kinesin-1-dependent hyp7 migration. This isoform-specific inhibition, combined with differential affinity for KLC-2, establishes a mechanism for achieving directional control of nuclear positioning during development. Together, these interdisciplinary studies reveal how alternative isoforms of cargo adaptors can generate developmental stage-specific regulation of motor activity.

  PublisherOA PDFDOI

• Giant KASH proteins and ribosomes establish distinct cytoplasmic biophysical properties in vivo

  Science Advances · 2025-09-10 · 2 citations

  articleOpen accessSenior authorCorresponding

  Understanding how cells control their biophysical properties during development remains a fundamental challenge. While macromolecular crowding affects multiple cellular processes in single cells, its regulation in living animals remains poorly understood. Using genetically encoded multimeric nanoparticles for in vivo rheology, we found that Caenorhabditis elegans tissues maintain mesoscale properties that differ from those observed across diverse systems, including bacteria, yeast species, and cultured mammalian cells. We identified two conserved mechanisms controlling particle mobility: Ribosome concentration, a known regulator of cytoplasmic crowding, works in concert with a previously unknown function for the giant KASH (Klarsicht/ANC-1/SYNE homology) protein ANC-1 in providing structural constraints through associating with the endoplasmic reticulum. These findings reveal mechanisms by which tissues establish and maintain distinct mesoscale properties, with implications for understanding cellular organization across species.

  PublisherDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-23

  preprintOpen access

  ABSTRACT 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 G enetically E ncoded M ultimeric (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 EDMD’s 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.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-07 · 1 citations

  preprintOpen accessSenior author

  SUMMARY 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-83a’s 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.

  PublisherOA PDFDOI

• Giant KASH proteins and ribosomes synergistically establish cytoplasmic biophysical properties <i>in vivo</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-12

  preprintOpen accessSenior author

  Abstract Understanding how cells control their biophysical properties during development remains a fundamental challenge. While cytoplasmic macromolecular crowding affects multiple cellular processes in single cells, its regulation in living animals remains poorly understood. Using genetically encoded multimeric nanoparticles for in vivo rheology, we discovered that C. elegans tissues maintain distinct cytoplasmic biophysical properties that differ from those observed across diverse systems, including bacteria, yeast species, and cultured mammalian cells. We identified two conserved mechanisms controlling cytoplasmic macromolecular diffusion: ribosome concentration, a known regulator of cytoplasmic crowding, works in concert with a previously unknown function for the giant KASH protein ANC-1 scaffolding the endoplasmic reticulum. These findings reveal mechanisms by which tissues establish and maintain distinct cytoplasmic biophysical properties, with implications for understanding cellular organization across species. One-Sentence Summary Living tissues maintain unique intracellular biophysical properties under the control of cytoplasmic constraints and crowding.

  PublisherDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-23 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT 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 .

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-15 · 3 citations

  preprintOpen access

  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 &gt;50 spectrin repeats and a C-terminal outer nuclear membrane-spanning KASH domain. N2G’s 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-1’s light chain, indicating N2G’s involvement with both actin and microtubules. The absence of N2G leads to embryonic lethality in mice, while cellular assays highlight N2G’s role in nuclear positioning across diverse biological contexts. However, the precise mechanisms underlying N2G-mediated nucleocytoskeletal coupling remain unclear. Here we study N2G’s 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 N2G’s dynamic role as a crosslinker between actin and microtubule cytoskeletons, offering insights into nuclear movement, a fundamental cellular process.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32GM020127

  NIH · $118k

• Mechanism of Nuclear migration.

  NIH · $4.5M · 2006–2021

• Mechanisms of Nuclear Migration

  NIH · $2.8M · 2020–2029

Frequent coauthors

• Min Han

  Weifang University

  37 shared

• Michael L. Goldberg

  Cornell University

  24 shared

• Gail L. Ackerman

  Harvard University

  16 shared

• R. Mark Grady

  St. Louis Children's Hospital

  16 shared

• Joshua R. Sanes

  Harvard University Press

  16 shared

• G. W. Gant Luxton

  University of California, Davis

  14 shared

• Tim J. Yen

  12 shared

• Natalie E. Cain

  The London College

  11 shared

Education

• PhD Genetics

  Cornell University

  1998

Awards & honors

• Annual Award and Citation Ceremony 2023
• Storer Lectureship in the Life Sciences