Linker cell death regulation in C. elegans

Information

  • Research Project
  • 10298197
  • ApplicationId
    10298197
  • Core Project Number
    R01HD103610
  • Full Project Number
    1R01HD103610-01A1
  • Serial Number
    103610
  • FOA Number
    PA-20-185
  • Sub Project Id
  • Project Start Date
    8/5/2021 - 2 years ago
  • Project End Date
    7/31/2026 - 2 years from now
  • Program Officer Name
    MUKHOPADHYAY, MAHUA
  • Budget Start Date
    8/5/2021 - 2 years ago
  • Budget End Date
    7/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    8/5/2021 - 2 years ago
Organizations

Linker cell death regulation in C. elegans

Our long-term goal is to understand the molecular basis of a novel morphologically-conserved non-apoptotic developmental cell-death program we uncovered, and to determine its roles in mammalian development and disease. Programmed cell death is a major cell fate. Apoptosis, an extensively studied cell death process, requires caspase proteases and is accompanied by chromatin compaction and cytoplasmic shrinkage. Surprisingly, mice lacking apoptotic effectors survive to adulthood. These observations suggest that non- apoptotic cell death may play key roles in animal development. Although genes promoting necrotic cell death have been described, these are not required for development. Thus, whether alternative developmental cell death pathways exist, and if so, what molecular mechanisms govern their execution, is a major outstanding question. Our studies of the C. elegans linker cell provide direct evidence that caspase-independent non- apoptotic cell death pathways operate during animal development. Linker cell death occurs in the absence of C. elegans caspases, and other apoptosis genes are also not required, nor are genes implicated in autophagy or necrosis. The morphology of a dying linker cell is characterized by lack of chromatin condensation, a crenellated nucleus, and swelling of cytoplasmic organelles. Remarkably, cell death with similar features (linker cell-type death, LCD) also occurs in vertebrates, and is characteristic of neuronal degeneration in polyglutamine diseases. We recently described a pathway governing C. elegans LCD. This is the first such framework for a non-apoptotic developmental cell-death program. LCD is controlled by Wnt signals that function in parallel with a developmental-timing and a MAPKK pathway to control non-canonical activity of HSF-1, a conserved heat-shock transcription factor. let-70/Ube2D2, encoding a conserved E2 ubiquitin- conjugating enzyme, is a key target of HSF-1. The E3 components CUL-3/cullin, RBX-1, BTBD-2, and EBAX-1 function with LET-70/UBE2D2 for LCD. Our recent evidence suggests that histone methylation may be a target of this pathway, likely resulting in genome-wide chromatin opening, allowing nuclease access and DNA degradation. LCD pathway components promote vertebrate cell-degenerative processes. pqn-41, a glutamine- rich protein, is reminiscent of polyQ proteins causing neurodegeneration. and tir-1/Sarm and BTBD-2 promote distal axon degeneration following axotomy, supporting conserved cell dismantling roles. We recently showed that treatment of mammalian cells with the kinase inhibitor staurosporin (STS) causes LCD like death. Here we will build on these studies to uncover LCD pathway targets, and study relevance to mammals. We will: (1) Investigate the role of SAMS-4, a BTBD-2 target, and NUC-1, a DNaseII enzyme, in LCD, and test an hypothesized pathway for these in chromatin modification and DNA degradation. (2) Identify EBAX-1 target genes and assess roles in LCD control. (3) Characterize STS-induced death in mammalian cells, define conservation with C. elegans LCD, and identify relevant genes.

IC Name
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
  • Activity
    R01
  • Administering IC
    HD
  • Application Type
    1
  • Direct Cost Amount
    215000
  • Indirect Cost Amount
    149425
  • Total Cost
    364425
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    865
  • Ed Inst. Type
  • Funding ICs
    NICHD:364425\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    DEV1
  • Study Section Name
    Development - 1 Study Section
  • Organization Name
    ROCKEFELLER UNIVERSITY
  • Organization Department
  • Organization DUNS
    071037113
  • Organization City
    NEW YORK
  • Organization State
    NY
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    100656399
  • Organization District
    UNITED STATES