Preprint  ·  2025

Non-apoptotic death of the C. elegans linker cell is primed by MYRF-1 activation of pqn-41/polyQ

Olya Yarychkivska,1,* Simin Liu (刘斯敏),1 Lauren Bayer Horowitz,1 Shiloh Newland,1 Peipei Wu,2 Saiya Mittal,1,† Shogo Tamura,1,† Tetiana Novosolova,1,† David Faulkner Ritter,3 Yun Lu,1 Sevinç Ercan,3 Christopher Hammell,2 and Shai Shaham1,*
* Co-corresponding authors  ·  † Equal contribution
1 Laboratory of Developmental Genetics, The Rockefeller University, New York, NY 10065, USA
2 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
3 Department of Biology and the Center for Genomics and Systems Biology, New York University, New York, NY 10003, USA
Correspondence: oyarychkiv@rockefeller.edu, shaham@rockefeller.edu

Linker cell-type death (LCD) is a morphologically conserved non-apoptotic cell-death process with features resembling polyglutamine-dependent neurodegeneration. In C. elegans development, LCD eliminates the male-specific linker cell following its long-range migration. Using single-cell mRNA sequencing of migrating and dying linker cells, we identify myrf-1, encoding a membrane-bound transcription factor implicated in human developmental disorders, as a key LCD regulator. MYRF-1 translocates to the linker cell nucleus during early migration and, surprisingly, its auxin-inducible degradation then, but not later, blocks LCD. MYRF-1 directly binds known LCD genes, including pqn-41, encoding an aggregation-prone polyglutamine protein. Deleting a bona fide MYRF-1-binding site within pqn-41 promotes linker cell survival. Our findings reveal that linker cell death is primed well before cell demise takes place, temporally uncoupling death commitment and execution.