The long-term objective of this project is to understand how genes specify the development and functioning of a behavioral system. The anatomically simple neuromuscular system of the nematode Caenorhabditis elegans consists of diverse types of neurons and muscles while being sufficiently small and simple to allow a complete description of its cells, neural circuits and cell lineage, facilitating the identificatio of anatomical and developmental lesions caused by mutations. Studies of the C. elegans egg-laying system and of the neuromuscular systems that control behaviors coordinately regulated with egg laying offer opportunities for the analysis of a broad variety of fundamental biological problems of relevance to many human disorders. In this project, mutants abnormal in the behavior of egg laying or in behaviors co-regulated with egg laying will be identified and analyzed to establish mechanisms that modulate C. elegans behavior in response to both the environment and experience. Methods of genetics, molecular biology, biochemistry, cell biology, electrophysiology and behavioral biology will be used. Two major questions will be addressed. First, what are the molecular, cellular and neural-circuit mechanisms that mediate behavioral responses to changes in oxygen concentration? Both acute and chronic oxygen deprivation have profound effects on cellular physiology and animal behavior. Oxygen deprivation is responsible for the cardiac damage in heart attacks, and the restoration of normal levels of oxygen after a period of oxygen deprivation is responsible for the neurological damage in ischemic strokes. The major pathway that mediates responses to chronic oxygen deprivation was discovered from studies of the C. elegans egg-laying system, has been implicated in many human disorders and has defined major therapeutic targets for ischemic disorders and cancer. This project will identify new components of this important pathway as well as reveal how this pathway controls animal behavior. Second, what are the molecular genetic mechanisms that control nervous system signaling to modulate behavior and define behavioral states? Nerve cells communicate with other nerve cells and with muscles by releasing and responding to chemical neurotransmitters and neuromodulators. This process is fundamental to all aspects of human action, perception, language, emotion and thought, and disruptions in this process are responsible for many neurologic and neuropsychiatric disorders. This project will analyze a newly discovered gene that functions in neurochemical signaling and is implicated in controlling a specific class of neuromodulator, neuropeptides, which are involved in many aspects of human physiology, including reproduction, growth, metabolism, sleep and memory as well as in the assumption of one of two alternative behavioral states, such as hunger-satiety, sleep-wakefulness and monogamy-polygamy.
An understanding of the fundamental mechanisms that control animal development and behavior is key to an understanding of many aspects of human health and disease. This project proposes to identify such mechanisms by analyzing the development and functioning of the egg-laying system of the experimentally tractable roundworm Caenorhabditis elegans, which shares many genetic, molecular and cellular features with more complicated animals, including humans.
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|de la Cruz, Ignacio Perez; Ma, Long; Horvitz, H Robert (2014) The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9. PLoS Genet 10:e1004175|
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|Hallem, Elissa A; Spencer, W Clay; McWhirter, Rebecca D et al. (2011) Receptor-type guanylate cyclase is required for carbon dioxide sensation by Caenorhabditis elegans. Proc Natl Acad Sci U S A 108:254-9|
|Saffer, Adam M; Kim, Dong Hyun; van Oudenaarden, Alexander et al. (2011) The Caenorhabditis elegans synthetic multivulva genes prevent ras pathway activation by tightly repressing global ectopic expression of lin-3 EGF. PLoS Genet 7:e1002418|
|Ma, Long; Tan, Zhiping; Teng, Yanling et al. (2011) In vivo effects on intron retention and exon skipping by the U2AF large subunit and SF1/BBP in the nematode Caenorhabditis elegans. RNA 17:2201-11|
|Tabuchi, Tomoko M; Deplancke, Bart; Osato, Naoki et al. (2011) Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex. PLoS Genet 7:e1002074|
|Korzelius, Jerome; The, Inge; Ruijtenberg, Suzan et al. (2011) C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability. Dev Biol 350:358-69|
|Davison, Ewa M; Saffer, Adam M; Huang, Linda S et al. (2011) The LIN-15A and LIN-56 transcriptional regulators interact to negatively regulate EGF/Ras signaling in Caenorhabditis elegans vulval cell-fate determination. Genetics 187:803-15|
|Ringstad, Niels; Abe, Namiko; Horvitz, H Robert (2009) Ligand-gated chloride channels are receptors for biogenic amines in C. elegans. Science 325:96-100|
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