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Elucidation of the mechanisms through which the neuropeptide receptor NMUR-1 mediates the sensory influence on C. elegans physiology and lifespan

English title Elucidation of the mechanisms through which the neuropeptide receptor NMUR-1 mediates the sensory influence on C. elegans physiology and lifespan
Applicant Alcedo Joy
Number 134958
Funding scheme Project funding (Div. I-III)
Research institution Department of Biological Sciences Wayne State University
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Genetics
Start/End 01.05.2011 - 30.04.2013
Approved amount 220'667.00
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All Disciplines (3)

Discipline
Genetics
Embryology, Developmental Biology
Molecular Biology

Keywords (5)

sensory influence on lifespan; neuropeptide receptor signaling; food-type recognition; sterol receptor signaling; C. elegans

Lay Summary (English)

Lead
Lay summary

Environmentalcues, like the type of food source, the level of food intake and many forms ofstress, have been shown to influence lifespan. These cues presumably modulatethe activities of signaling pathways that have previously been shown to affectlongevity. However, the mechanisms involved in integrating different types ofenvironmental information with these signaling pathways remain unknown.

In the worm C. elegans, at least a part of these interactions is mediated by the sensory system.  A subset of neurons that function in taste and smell has been shown to shorten worm lifespan, whereas a different subset of taste neurons lengthens its lifespan.  This suggests that sensory neurons can mediate the lifespan effects of specific food-derived cues.  Consistent with this hypothesis, some of its bacterial food sources, like different E. coli strains, have also been shown to have different effects on C. elegans longevity.

Recently, we have shown that C. elegans sensory neurons affect lifespan through recognition of food types.  We have also found that these neurons act with a neuropeptide receptor, which is similar to neuromedin U receptors in humans.  Moreover, we have shown that this receptor, which is expressed in both the sensory system and the reproductive system, influences C. elegans lifespan in a manner dependent on the lipopolysaccharide (LPS) structure of its live E. coli food source.

Although our data suggest that this neuropeptide receptor, NMUR-1, is required in processing the information derived from specific food cues to influence lifespan, the precise mechanisms involved remain unclear.  Thus, we aim to understand the mechanisms through which NMUR-1 mediates the sensory influence on lifespan and alters C. elegans physiology in a food source-dependent manner.  We plan to:

(1) identify the cellular sites of NMUR-1 function, which should also help determine the type of sensory cues that might regulate its activity;

(2) determine how NMUR-1 regulates the different signaling activities of a sterol hormone receptor, which is required for NMUR-1 activity on the different food sources; and

(3) identify the transcriptional targets of the NMUR-1 pathway to determine how this pathway integrates environmental information and regulate physiological responses that affect lifespan.

Our discovery of a role for NMUR-1 in affecting C. elegans lifespan in a food source-dependent manner, together with the sensory system, provides a genetic framework from which one can elucidate the mechanisms that underlie the effects of specific food cues and the sensory influence on lifespan.  Since this receptor is also found in humans, understanding how it affects C. elegans lifespan in a food source-dependent manner may lead us to understand how a similar pathway could function within us.  Accordingly, the studies addressed in this grant proposal may also yield much needed insight into how different types of diet contribute to age-related diseases, like obesity and diabetes, which are prevalent within our population.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Neuronal inputs and outputs of aging and longevity
Alcedo Joy, Flatt Thomas, Pasyukova Elena G. (2013), Neuronal inputs and outputs of aging and longevity, in Front. Genet. , 4, 71.
Molecular and cellular circuits underlying C. elegans olfactory plasticity
Alcedo Joy, Zhang Yun, Molecular and cellular circuits underlying C. elegans olfactory plasticity, in Benjamin Paul R, Menzel Randolf (ed.), Elsevier/Academic Press, San Diego, California.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Nineteenth C. elegans International Worm Meeting, Los Angeles, California 19.04.2013 Los Angeles, California, registered on April 19, 2013
Thirteenth International Congress on Invertebrate Reproduction and Development 05.04.2013 Detroit, Michigan, registered on April 5, 2013
C. elegans Topic Meeting on Neuronal Development, Synaptic Function & Behavior, Heidelberg, Germany 14.06.2012 Heidelberg, Germany
EU Network of Excellence: Young Investigators Workshop Lifespan – Genes and Ageing, Paris, France 02.08.2011 Paris, France
Eighteenth C. elegans International Worm Meeting, Los Angeles, California 22.06.2011 Los Angeles, California


Abstract

Environmental cues, like the type of food source (Garsin et al., 2003, Science 300, 1921; Mair et al., 2005, PLoS Biol 3, e223), the level of food intake (Klass, 1977) and many forms of stress, have been shown to influence lifespan. These cues presumably modulate the activities of signaling pathways that have previously been found to affect longevity. However, the mechanisms involved in integrating different types of environmental information with these signaling pathways remain unknown.In C. elegans, at least a part of these interactions is mediated by the sensory system (Apfeld and Kenyon, 1999; Alcedo and Kenyon, 2004). A subset of gustatory and olfactory neurons has been shown to exert distinct effects on lifespan (Alcedo and Kenyon, 2004), which suggests that these neurons mediate the lifespan effects of specific food-derived cues. Consistent with this hypothesis, some of its bacterial food sources have also been shown to have different effects on C. elegans longevity (Garsin et al., 2003). Recently, we have shown that sensory neurons influence lifespan through food-type recognition, which is distinct from food-level restriction [commonly known as calorie restriction; (Maier et al., 2010)]. We also identified nmur-1, a gene that encodes a putative neuropeptide receptor homologous to mammalian neuromedin U receptors (Howard et al., 2000), to be involved in this process (Maier et al., 2010). Moreover, we have shown that nmur-1, which is expressed in the somatic gonad, sensory neurons and interneurons, influences C. elegans lifespan in a manner dependent on the lipopolysaccharide (LPS) structure of its live E. coli food source (Maier et al., 2010).Although our data suggest that nmur-1 is required in processing the information derived from specific food cues to influence lifespan, the precise mechanisms involved remain unclear. Thus, we aim to understand the cellular and molecular bases through which NMUR-1 mediates the sensory influence on lifespan and alters C. elegans physiology in a food source-dependent manner. We plan to:(1)identify the cellular sites of nmur-1 function, which should also help determine the type of sensory cues that might regulate nmur-1 activity;(2)determine how NMUR-1 regulates the different signaling activities of the sterol receptor DAF-12, which we have recently found is completely required for the NMUR-1 effect on lifespan on the different food sources; and(3)identify the transcriptional targets of the NMUR-1/DAF-12 pathway to determine how this pathway integrates environmental information and regulate physiological responses that affect lifespan.Our discovery of the gene, nmur-1, that affects C. elegans lifespan in a food source-dependent manner, and in concert with the sensory system, provides a genetic framework from which one can elucidate the mechanisms that underlie the effects of specific food cues, as well as those of the sensory system, on lifespan. Since nmur-1 is conserved in mammals, the elucidation of how nmur-1 affects C. elegans lifespan in a food source-dependent manner may lead to the elucidation of a similar pathway in these higher organisms. Finally, the studies addressed in this proposal may also yield much needed insight into how different types of diet contribute to age-related diseases, like obesity and diabetes, which are prevalent within our population.
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