One of the most devastating birth defects affect the neural crest, a highly migratory stem cell-like population that contribute to craniofacial and cardiovascular development, and peripheral and enteric nervous system assembly. Cell lineage tracing and tissue transplantation studies have revealed the neural crest cell (NCC) migratory pathways emerge as discrete segregated streams, separated by neural-crest-free exclusion zones that appear to prevent the intermixing of NCC subpopulations and ensure their arrival at precise targets. These findings support the premise that neural crest cell guidance cues derive from the embryonic microenvironment and cell communication. Most noteworthy are the data we have generated in vivo showing cell-cell and cell-environment interactions may influence the directional migration of the neural crest. Based on these observations, we propose to test the central hypothesis that the microenvironment and cell-cell interactions associated with the neural crest-rich regions of the embryo contain informational cues with the potential to direct cells to precise targets. Our long term goal is to understand the biological mechanisms underlying neural crest migration that ultimately results in organ development. Our short term goal is to identify the key cellular and molecular mechanisms underlying the sculpting of cranial NCC migratory streams within an in vivo model. Using in vivo molecular perturbations and embryo microsurgery, together with photoactivation cell labeling, 4-D confocal imaging, cell tracking and cell behavior analyses, we propose to:
Aim 1 : Characterize the specific and dynamic cellular interactions essential for cranial neural crest migration using in vivo photoactivation cell labeling, 4-D confocal imaging, cell tracking and cell behavior analyses.
Aim 2 : To determine the role of neuropilins within the embryonic microenvironment in signaling and modulating neural crest migration.
Aim 3 : Investigate the role of the embryonic microenvironment in signaling and modulating neural crest migration, with particular focus on neuropilin- semaphorin and neuropilin-VEGF interactions. Public Health Relevance: At the completion of these studies, we expect to have an increased understanding of guidance cues and pathways that directly modulate neural crest migration that could be translated for novel therapeutic applications.
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|Bailey, Caleb M; Kulesa, Paul M (2014) Dynamic interactions between cancer cells and the embryonic microenvironment regulate cell invasion and reveal EphB6 as a metastasis suppressor. Mol Cancer Res 12:1303-13|
|Wynn, Michelle L; Rupp, Paul; Trainor, Paul A et al. (2013) Follow-the-leader cell migration requires biased cell-cell contact and local microenvironmental signals. Phys Biol 10:035003|
|Kulesa, Paul M; McKinney, Mary C; McLennan, Rebecca (2013) Developmental imaging: the avian embryo hatches to the challenge. Birth Defects Res C Embryo Today 99:121-33|
|McKinney, Mary C; Fukatsu, Kazumi; Morrison, Jason et al. (2013) Evidence for dynamic rearrangements but lack of fate or position restrictions in premigratory avian trunk neural crest. Development 140:820-30|
|Ridenour, Dennis A; McKinney, Mary Cathleen; Bailey, Caleb M et al. (2012) CycleTrak: a novel system for the semi-automated analysis of cell cycle dynamics. Dev Biol 365:189-95|
|Wynn, Michelle L; Kulesa, Paul M; Schnell, Santiago (2012) Computational modelling of cell chain migration reveals mechanisms that sustain follow-the-leader behaviour. J R Soc Interface 9:1576-88|
|McKinney, Mary Cathleen; Kulesa, Paul M (2011) In vivo calcium dynamics during neural crest cell migration and patterning using GCaMP3. Dev Biol 358:309-17|
|McKinney, Mary Cathleen; Stark, Danny A; Teddy, Jessica et al. (2011) Neural crest cell communication involves an exchange of cytoplasmic material through cellular bridges revealed by photoconversion of KikGR. Dev Dyn 240:1391-401|
|Steen, Joseph; Morrison, Jason A; Kulesa, Paul M (2010) Multi-position photoactivation and multi-time acquisition for large-scale cell tracing in avian embryos. Cold Spring Harb Protoc 2010:pdb.prot5447|
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