L1CAMs are a family of immunoglobulin cell adhesion molecules that play important roles in the development of nervous system, including axon guidance and morphogenesis as well as axon myelination. Mutations in L1CAMs are directly linked to the neurological L1 syndrome, the symptoms of which include mental retardation and hydrocephalus. In addition, L1CAMs are implicated in neurosychiatric disorders, including schizophrenia, the autistic spectrum disorder, and addiction. One salient feature of L1CAM-associated diseases is that they are heterogeneous and genetically complex and subject to genetic modification, pointing to the existence of as-yet-unidentified functions for L1CAMs that are likely masked by genetic compensatory mechanisms. As transmembrane proteins, L1CAMs sit on the plasma membrane and thus are primed to integrate extracellular signals, converting them into cellular responses that require cross-talk with the cytoskeletal and intracellular signaling networks. Molecular mechanisms by which cell adhesion receptors relay these signals are just beginning to be uncovered, but much is still unknown. This application seeks to fill these gaps, identifying previously- uncharacterized L1CAM functions in synaptic regulation and defining the molecular mechanisms by which L1CAMs are functionally linked to intracellular signaling networks. We have established C. elegans as a powerful genetic system to dissect the roles and mechanisms of L1CAMs. In our previous studies, we determined that the C. elegans L1CAMs, SAX-7 LAD-2 function in maintaining nervous system integrity and axon guidance respectively. We have made significant inroads into defining L1CAM mechanisms of action that are remarkably conserved between mammals and C. elegans. Our recent studies, which took advantage of the ability to easily conduct modifier screens in C. elegans, identified the interplay between the mitogen-activated protein kinase (MAPK) signaling cascade and L1CAMs in an unexpected role in synaptic regulation. To better define the molecular mechanisms that link L1CAMs and MAPK to the synaptic machinery, our aims are 1) to define the roles of SAX-7 and MAPK in the synaptic vesicle cycle, 2) to resolve how SAX-7 and MAPK-1 coordinately regulate synaptic function, and 3) to define the factors that mediate SAX-7 and MAPK roles in synaptic transmission. With L1CAMs and MAPK implicated in both intellectual disability and the autism spectrum, this basic research in C. elegans will reveal fundamental knowledge on synaptic modulation that will provide additional insight into mechanisms underlying human neuropsychiatric disorders.

Public Health Relevance

L1CAMs are associated with the neurological L1 Syndrome as well as neuropsychiatric diseases including schizophrenia, autistic spectrum disorder, and susceptibility to addiction. The use of model organisms to study the biology of L1CAM-associated diseases is essential, since technical and ethical issues of human studies limit our mechanistic understanding of L1CAMs. Because of the extensive evolutionary conservation of L1CAMs, this proposed study in C. elegans will contribute key mechanistic insight of L1CAM function and the biology underlying these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045873-11
Application #
9632851
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Riddle, Robert D
Project Start
2005-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Dong, Bingyun; Moseley-Alldredge, Melinda; Schwieterman, Alicia A et al. (2016) EFN-4 functions in LAD-2-mediated axon guidance in Caenorhabditis elegans. Development 143:1182-91
Yochem, John; La┼żeti?, Vladimir; Bell, Leslie et al. (2015) C. elegans NIMA-related kinases NEKL-2 and NEKL-3 are required for the completion of molting. Dev Biol 398:255-66
Opperman, Karla; Moseley-Alldredge, Melinda; Yochem, John et al. (2015) A novel nondevelopmental role of the sax-7/L1CAM cell adhesion molecule in synaptic regulation in Caenorhabditis elegans. Genetics 199:497-509
Kang, Yuan-Lin; Yochem, John; Bell, Leslie et al. (2013) Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1. Mol Biol Cell 24:308-18
Stawicki, Tamara M; Zhou, Keming; Yochem, John et al. (2011) TRPM channels modulate epileptic-like convulsions via systemic ion homeostasis. Curr Biol 21:883-8
Zhou, Shan; Chen, Lihsia (2011) Neural integrity is maintained by dystrophin in C. elegans. J Cell Biol 192:349-63
Chen, Lihsia; Zhou, Shan (2010) ""CRASH""ing with the worm: insights into L1CAM functions and mechanisms. Dev Dyn 239:1490-501
Zhou, Shan; Opperman, Karla; Wang, Xuelin et al. (2008) unc-44 Ankyrin and stn-2 gamma-syntrophin regulate sax-7 L1CAM function in maintaining neuronal positioning in Caenorhabditis elegans. Genetics 180:1429-43
Wang, Xuelin; Zhang, Wei; Cheever, Thomas et al. (2008) The C. elegans L1CAM homologue LAD-2 functions as a coreceptor in MAB-20/Sema2 mediated axon guidance. J Cell Biol 180:233-46