Neural control of cell stress response pathways and transcription factors

The nervous system controls somatic physiology, development, and tissue regeneration and also drives aging, and progression of diseases such as cancer. Yet, the governing principles, rules of interaction between nerves and non-neural tissues, and mechanisms remain largely unknown.

Over a decade ago, we discovered that the Caenorhabditis elegans nervous system controls when and whether other cells within the body of the animal activate their heat-shock response. This was surprising since the so-called ‘heat-shock response’ is a defense program against protein misfolding fundamental to all functions of a cell, and long considered to be controlled autonomously, by the cell in which misfolding occurred.

My lab has since investigated how neuronal signals control conserved stress-responsive transcription programs of other cells, both neuronal and non-neural. We have made seminal contributions in this area.

Figure from a scientific research study
Neurons can turn HSF1 ‘ON’: We can mimic heat shock by activating thermosensory neurons, even in the absence of any temperature increase (see Tatum et al, Curr Biol. 2015).
Figure from a scientific research study
Serotonin is a stress signal released upon thermosensory neuronal activation in C. elegans (see Tatum et al, Curr Biol. 2015, Das et al, Elife 2020, Cruz-Corchado et al, G3 2020)
Figure from a scientific research study
Serotonin signaling mediates a conserved signal transduction pathway to activate HSF1 through FACT recruitment to hsp genes (see Das et al, Elife 2020).

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An emerging theme

Our studies demonstrate that in a metazoan, neuronal networks repress – and subsequently de-repress – stress response pathways that can be activated autonomously in isolated cells, thereby co-opting these defense programs of cells to cephalic control.

Our working model is that cell stress programs can be:

  • Activated pre-emptively, by perceived threats, before damage occurs; and
  • Activated unnecessarily even when the ‘real’ danger has subsided
Figure from a scientific research study
The perception of a threat can preemptively activate HSF1 (see Ooi et al, Sci. Signal 2017)

What we’ve learned

Cephalic control over the transcription factor HSF1 is sufficient to:

  • Upregulate molecular chaperones;
  • Suppress protein misfolding; and
  • Establish HSF1-induced durable epigenetic changes in cells that receive the neuronal signal

We’ve also learned that in C. elegans persist over two generations, through epigenetic mechanisms also conserved in mammalian cells.

Recently, we found another important stress response pathway is also controlled by C. elegans neurons:

  • Control the DNA-damage independent activation of the tumor suppressor p53-ortholog in larval pluripotent blast cells through the neuronal release of the C. elegans IL-17 cytokine; and
  • Determine whether larvae arrest in dormancy or grow to reproductive adults.

What we’re learning

These discoveries have led to the establishment of two major research projects in the lab, where we use the metazoan model C. elegans, mammalian cell culture, and mouse models to address questions.

Figure from a scientific research study

Project 1: Control of the heat shock transcription factor in cells of a metazoan

See the science

Figure from a scientific research study

Project 2: The roles of IL-17/ILC-17.1 and CEP-1/p53 in development, aging, and dormancy

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Connect with the Prahlad Lab

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Department of Cell Stress Biology 
Roswell Park Comprehensive Cancer Center  
Elm and Carlton Streets  
Buffalo, NY 14263