Abstract

Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex that plays a critical role in cytoplasmic cargo trafficking, including Rab-mediated endosomal recycling and lysosomal degradation. LIC1 interacts with various cargo adaptors, such as RILPL1 and RILPL2, to regulate these processes, and defects in this gene are predicted to impair dynein motor function, Rab binding, and lysosomal trafficking. Here, we identified a dync1li1 zebrafish mutant with a premature stop codon at the exon 12/13 splice acceptor site, that exhibits increased angiogenesis. In vitro, LIC1-deficient human endothelial cells show elevated cell surface levels of the pro-angiogenic receptor VEGFR2, increased SRC phosphorylation, and enhanced Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a in zebrafish mimics the excessive angiogenesis seen in dync1li1 mutants. Similarly, zebrafish harboring mutations in rilpl1/2, which facilitate Rab docking to LIC1 for lysosomal targeting, also display increased angiogenesis. These results indicate that LIC1, alongside RILPL1 and RILPL2, restricts angiogenesis not only by modulating endosomal recycling but also by promoting lysosomal trafficking and degradation of VEGFR2-containing endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting shifts the balance toward increased Rab11-mediated endosome recycling activity, driving excessive SRC signaling and contributing to aberrant angiogenesis.

Committee Chair

Robert Mecham

Committee Members

Amber Startman; Carmen Halabi; Charles Kaufman; Jonathan Cooper; Robert Mecham

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-7-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-4035-0617

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