Cawthon, Bryan et al. (2015) International Worm Meeting "Investigating the Potential Role of the Transcription factor FKH-8 in Dopamine Metabolism."

Cawthon, Bryan, Nelms, Brian

[International Worm Meeting, 2015]

Signaling through the neurotransmitter dopamine (DA) is critical for fundamental life processes across the animal kingdom, including motor control, behavior, and cognition. Disruption of DA function is associated with problems in motor activity (tremors, rigidity, etc.) such as occurs with the progressive neurodegeneration of DA neurons in Parkinson's disease. Understanding the modulation of DA neuron function, which can occur through control of DA synthesis, vesicle packaging, release, reception, reuptake, and/or metabolism, will give insight into new therapeutic strategies for DA-associated disorders.We are using Caenorhabditis elegans as a model to investigate the modulation of DA signaling. Our lab has discovered an important role for the transcription factor FKH-8 in C. elegans DA neuron function, as evidenced by a DA-dependent swimming-induced paralysis (SWIP) phenotype in mutants lacking FKH-8. The forkhead gene family encodes winged-helix transcription factors. One potential aspect of DA signaling regulation that I am exploring is regulation of DA metabolism by monoamine oxidases (MAOs), which help to degrade DA by clearing it from the synapse. It is possible that the hyper-dopaminergic phenotype of fkh-8 mutants is due to a downstream loss of MAOs. Our initial data suggests that mutants for any of the 3 MAO-encoding genes (amx-1, -2, or -3) display a SWIP phenotype, and we are currently generating fkh-8;amx double mutant strains to determine if these genes are in the same pathway.Grant Number: 1R25GM107754-01 (NIH)Project Title: The Fisk-Vanderbilt Biomedical Bridge to the Doctorate.

Garrett, Destane et al. (2017) International Worm Meeting "The transcription factor fkh-8 is involved in sustaining CO2 function in C. elegans."

Nelms, Brian, Garrett, Destane, Cawthon, Bryan

[International Worm Meeting, 2017]

Sensing and responding to changing levels of oxygen and carbon dioxide is an important function across the animal kingdom. In the model organism Caenorhabditis elegans, the inability to sense fluctuations in CO2 levels can potentially lead to death. The BAG neuron is one cell type that can function as a mediator of high CO2 avoidance and can sense decreases in O2 levels. Some transcription factors, such as ETS-5 and EGL-13, are already known to be required for BAG neuron CO2 and O2 sensing. We have observed through genetics and behavioral studies that the transcription factor FKH-8 likely also plays a role in CO2 sensing. We are more specifically studying the role of FKH-8 in regulating BAG neuron gene expression by examining expression decreases or increases in specific BAG neuron reporter genes in fkh-8 mutants. Through these experiments, we hope to identify which important signaling components in BAG neuron CO2-sensing are controlled by FKH-8.

Calero M et al. (2001) J Biol Chem "Yop1p, the yeast homolog of the polyposis locus protein 1, interacts with Yip1p and negatively regulates cell growth."

Calero M, Collins RN, Whittaker GR

[J Biol Chem, 2001]

Rab proteins are small GTPases that are essential elements of the protein transport machinery of eukaryotic cells. Each round of membrane transport requires a cycle of Rab protein nucleotide binding and hydrolysis. We have recently characterized a protein, Yip1p, which appears to play a role in Rab-mediated membrane transport in Saccharomyces cerevisiae. In this study, we report the identification of a Yip1p-associated protein, Yop1p. Yop1p is a membrane protein with a hydrophilic region at its N terminus through which it interacts specifically with the cytosolic domain of Yip1p. Yop1p could also be coprecipitated with Rab proteins from total cellular lysates. The TB2 gene is the human homolog of Yop1p (Kinzler, K. W., Nilbert, M. C., Su, L.-K., Vogelstein, B., Bryan, T. M., Levey, D. B., Smith, K. J., Preisinger, A. C., Hedge, P., McKechnie, D., Finniear, R., Markham, A., Groffen, J., Boguski, M. S., Altschul, S. F., Horii, A., Ando, H. M., Y., Miki, Y., Nishisho, I., and Nakamura, Y. (1991) Science 253, 661-665). Our data demonstrate that Yop1p negatively regulates cell growth. Disruption of YOP1 has no apparent effect on cell viability, while overexpression results in cell death, accumulation of internal cell membranes, and a block in membrane traffic. These results suggest that Yop1p acts in conjunction with Yip1p to mediate a common step in membrane traffic.