Notch signaling plays well described roles in developmental cell fate decisions, in the regulation of stem cell proliferation and in numerous diseases. However, Notch signaling is also critical for the function of adult neurons. Notch plays a role in memory retention in mice and Drosophila, yet the targets of Notch signaling in neurons are unclear. We have demonstrated that the C. elegans lin-12 Notch receptor acts in adult animals to modulate behavior. In the studies proposed here, we will identify the molecular pathways by which Notch signaling alters neuronal function and behavior using the powerful genetic techniques available in C. elegans. In a pilot screen, we identified five genes expressed in the nervous system that are likely direct targets of Notch. All five genes encode proteins that are likely critical for Notch signaling in vertebrate neurons as well. In this proposal, we address the mechanisms and pathways by which these Notch target genes act in the adult nervous system to regulate neuronal activity and behavior.
Notch signaling is critical for normal function of the human nervous system. Mutations in Notch3 and Jagged1 cause CADASIL and Alagille syndromes, respectively. These are dominantly inherited disorders associated with stroke and dementia. Combined, their incidence is at least 1 in 50,000, although CADASIL is likely under-diagnosed. Recent evidence also suggests that Notch signaling is up-regulated in Down's syndrome patients. Interestingly, Notch and amyloid precursor proteins directly interact suggesting that Notch signaling may be important in the memory defects associated with Alzheimer's disease. There is no effective treatment for these disorders. Given the conservation across species of Notch regulatory mechanisms and targets, we anticipate that identifying the targets of Notch signaling in C. elegans will reveal be critical targets of Notch modulation in humans that are relevant in both normal and pathological conditions.
|Anderson, Edward N; Corkins, Mark E; Li, Jia-Cheng et al. (2016) C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins. Mech Ageing Dev 154:30-42|
|Fry, Amanda L; Laboy, Jocelyn T; Huang, Huiyan et al. (2016) A Conserved GEF for Rho-Family GTPases Acts in an EGF Signaling Pathway to Promote Sleep-like Quiescence in Caenorhabditis elegans. Genetics 202:1153-66|
|Chalfie, Martin; Hart, Anne C; Rankin, Catharine H et al. (2014) Assaying mechanosensation. WormBook :|
|Singh, Komudi; Ju, Jennifer Y; Walsh, Melissa B et al. (2014) Deep conservation of genes required for both Drosphila melanogaster and Caenorhabditis elegans sleep includes a role for dopaminergic signaling. Sleep 37:1439-51|
|Singh, Komudi; Huang, Huiyan; Hart, Anne C (2013) Do C. elegans sleep? A closer look. Sleep 36:307-8|
|Hyde, R; Corkins, M E; Somers, G A et al. (2011) PKC-1 acts with the ERK MAPK signaling pathway to regulate Caenorhabditis elegans mechanosensory response. Genes Brain Behav 10:286-98|
|Singh, Komudi; Chao, Michael Y; Somers, Gerard A et al. (2011) C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence. Curr Biol 21:825-34|
|Haspel, Gal; O'Donovan, Michael J; Hart, Anne C (2010) Motoneurons dedicated to either forward or backward locomotion in the nematode Caenorhabditis elegans. J Neurosci 30:11151-6|
|Guo, Zengcai V; Hart, Anne C; Ramanathan, Sharad (2009) Optical interrogation of neural circuits in Caenorhabditis elegans. Nat Methods 6:891-6|