Can neural signals override cellular decisions in the presence of DNA damage?

Abstract

Cells within an organism are in constant crosstalk with their surrounding environment. Short and long-range signals influence cellular behavior associated with division, differentiation, and death. This crosstalk among cells underlies tissue renewal to guarantee faithful replacement of old or damaged cells over many years. Renewing tissues also offer recurrent opportunities for DNA damage and cellular transformation that tend to occur with aging. Most cells with extensive DNA damage have limited options such as halting cell cycle to repair DNA, undergo senescence, or programmed cell death. However, in some cases cells carrying toxic forms of DNA damage survive and proliferate. The underlying factors driving survival and proliferation of cells with DNA damage remain unknown. Here we discuss potential roles the nervous system may play in influencing the fate of cells with DNA damage. We present a brief survey highlighting the implications the nervous system has in regeneration, regulation of stem cells, modulation of the immune system, and its contribution to cancer progression. Finally, we propose the use of planarian flatworms as a convenient model organism to molecularly dissect the influence of neural signals over cellular fate regulation in the presence of DNA damage.

Keywords: Animal models; DNA damage response; Nervous system; Neural regulation; Planarians; Stem cells.

Figure 1:. Cellular fate in the presence of DNA Double Stranded Break.

Schematic representation summarizing the different options cells with DNA double stranded breaks (DSBs) may take. The conventional paths (grey boxes) consist of cell cycle arrest with repair of DNA, senescence, and apoptosis. An alternative fourth path (red box) is characterized by cellular survival with DSBs and eventually division with DSBs. We propose neural signals may contribute to the survival and proliferation of cells with DSBs.

Figure 2:. A crosstalk between the body systems and cancer.

Illustration summarizing a hypothetical influence of neural signals over the immune system and cancer cells. (A) Neural signals are capable of suppressing TNF production. Depending on the adrenergic receptors that innate and adaptive immune cells contain neural signals can either limit or enhance the production of inflammatory cytokines. (B) Neural signals are capable of influencing cancer by promoting growth of cells through activation of EGFR-AKT pathway. A variety of neural cell types can influence invasion and angiogenesis.

Figure 3:. Neural signals promote the survival and proliferation of cells with DSBs.

Illustration summarizing the study in which genetic disruption of rad51 leads to a decrease in neoblast proliferation. (A) Represents a control animal with normal dividing cells (red dots). Genetic disruption of Rad51 leads to a systemic increase in cells with DSBs and cell death in the posterior region (not shown). The reduction in Rad51 function is accompanied by decrease of dividing cells that are mostly concentrated in the anterior region of the animal. Importantly, all dividing cells have high levels of DSBs. (B) Genetic disruption of β-catenin leads to bipolar headed animals (i.e., one head in each end and no posterior region). Genetic disruption of apc leads to bipolar tailed animals (i.e., organisms with only posterior regions and no heads). Disruption of rad51 was done on both bipolar headed animals and bipolar tailed animals. Comparison of dividing cells showed that bipolar headed animals had more cells dividing with DSBs than in the double tailed animal. Ectopic brain tissue was induced by disrupting the gene nou-darake (ndk) (Cebria et al., 2002) in double tailed animals subjected to Rad51(RNAi). Interestingly, the presence of brain tissue in a double tailed animal led to an increase in cell division with DSBs and most of the proliferative cells were located surrounding the brain. For more information see Peiris et al., 2016.