Chemosensory neurons specialized for the detection of carbon dioxide (CO2), a major product of aerobic metabolism, are present in the nervous systems of diverse animals. In vertebrates these neurons regulate breathing rhythms, and defects in CO2-sensing brain circuits are thought to underlie neurological disorders such as apneas and Sudden Infant Death Syndrome. Despite the critical roles that CO2-sensing neurons play in physiology, the molecular mechanisms required for their development and function remain poorly understood. Through genetic and physiological studies of CO2-sensing neurons of the nematode C. elegans we have established a powerful model for the study of such mechanisms. We have discovered that CO2-sensing neurons of C. elegans mediate a pathogen-avoidance behavior and require a Toll-like receptor (TLR) and its associated signaling pathway for their function. TLRs are evolutionarily conserved receptors that canonically function in embryonic patterning and innate immunity, and also function in the vertebrate nervous system to mediate inflammation. Our data indicate a previously unknown function for TLRs in the differentiation and function of sensory neurons and suggest a new role for TLRs in the vertebrate nervous system. Here we propose experiments to determine the molecular mechanisms by which TLR signaling promotes the differentiation and function of CO2-sensing neurons. These mechanisms will involve molecules required for TLR signaling, which is well known to play important roles in inflammation in the vertebrate brain and which our data suggest might also function in neuronal differentiation, as well as new components of the chemotransduction apparatus used for CO2-sensing.
Chemosensory neurons that detect carbon dioxide play critical roles in animal physiology; in mammals these neurons regulate the respiratory motor program to meet metabolic demand. Our studies of CO2- sensing neurons have revealed that Toll-like Receptor (TLR) signaling, which is critical for innate immunity and inflammation, is required for chemotransduction and regulates gene expression in CO2-sensing neurons. The proposed studies will determine molecular mechanisms of CO2-chemosensing, which will advance our understanding of neurological disorders characterized by respiratory failure such as Sudden Infant Death Syndrome and apneas, and also determine new mechanisms that function in TLR signaling that promotes the development and function of neurons.
| Martínez-Velázquez, Luis A; Ringstad, Niels (2018) Antagonistic regulation of trafficking to Caenorhabditis elegans sensory cilia by a Retinal Degeneration 3 homolog and retromer. Proc Natl Acad Sci U S A 115:E438-E447 |
| Zang, Kara E; Ho, Elver; Ringstad, Niels (2017) Inhibitory peptidergic modulation of C. elegans serotonin neurons is gated by T-type calcium channels. Elife 6: |
| Brandt, Julia P; Ringstad, Niels (2015) Toll-like Receptor Signaling Promotes Development and Function of Sensory Neurons Required for a C. elegans Pathogen-Avoidance Behavior. Curr Biol 25:2228-37 |
