Cell adhesion receptors are essential in multiple processes during animal development that range from tissue boundary formation and cell migration to more steady state processes such as maintenance of tissue integrity. Impaired cell adhesion receptors have been shown to be the underlying cause for many developmental disorders and cancer progression. As transmembrane proteins, cell adhesion receptors 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. The mechanisms by which cell adhesion receptors relay these signals are just beginning to be uncovered, but much is still unknown, particularly with those belonging to the immunoglobulin superfamily. The complex protein interactions mediated by immunoglobulin-like cell adhesion molecules (IgCAMs), which can form cell-cell and cell-extracellular matrix (ECM) interactions, have complicated analysis of IgCAM functions and mechanisms. As a model to better understand how IgCAMs function, we have focused our studies on dissecting the mechanistic roles of the L1 family of cell adhesion molecules (L1CAMs), which are associated with diverse cancers and the CRASH neurological disorder. 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, LAD-2 and LAD-1/SAX-7 function respectively in axon guidance and maintaining nervous system integrity. We have started to make inroads into L1CAM mechanisms, defining interactions that impact L1CAM-processes in a whole animal context. Our studies have identified extracellular cues as well as multiple cytoskeletal and intracellular signaling proteins that L1CAMs use to mediate their functions but how these interactions are coordinated to induce a cellular response is still unknown. Hence we will 1) dissect how LAD-2 mediates axon guidance via extracellular cues and the downstream LAD-2 molecules, 2) define how the multiple interactions with cytoskeletal and signaling protein interactions regulate LAD-1/SAX-7 activity, and 3) determine LAD-1/SAX-7 roles in the epithelia.

Public Health Relevance

L1CAMs are associated with diverse cancers and neurological disorders, including mental retardation, autism, and schizophrenia. Mutations in the human L1 gene result in the CRASH neurological disorder, the symptoms of which include corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus. Because of the extensive evolutionary conservation of L1CAMs, these studies in C. elegans will define mechanisms that control L1CAM function and provide insights into the physiological mechanism of these disorders, which will help lead to therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045873-08
Application #
8323450
Study Section
Intercellular Interactions (ICI)
Program Officer
Riddle, Robert D
Project Start
2003-04-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$291,336
Indirect Cost
$98,398
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Zhou, Shan; Chen, Lihsia (2011) Neural integrity is maintained by dystrophin in C. elegans. J Cell Biol 192:349-63
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
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