Multiscale mechanisms of cell migration during development: theory and experiment

INTRODUCTION Prevailing models of long-distance cell migration involve multicellular streams that are sculpted by dynamic cell-cell contacts and local inhibitory signals (Abercrombie, 1979; Teddy and Kulesa, 2004; Young et al., 2004; Druckenbrod and Epstein, 2007; Theveneau and Mayor, 2011; Darnton et al., 2010; Huang, 2009; Murase and Horwitz, 2004). In these models, cell movement is encouraged by cell-cell contact, which may be manifested as nudging from behind (Davis and Trinkaus, 1981) or the detachment of cells at the front of a migratory cell sheet (Carmona-Fontaine et al., 2008) to create space. These cell behaviors alone may not produce directional movement of a multicellular stream, but when local inhibitory signals restrict cell movements the result can be long-distance directed cell movement. By contrast, other models suggest that cells respond to chemotactic signals that drive the directional migration of individual cells (Dormann and Weijer, 2003; Richardson and Lehmann, 2010; Tarbashevich and Raz, 2010; Kulesa et al., 2010; Roussos et al., 2011; Cai et al., 2012) or cell clusters (Valentin et al., 2007; Aman and Piotrowski, 2010; Streichan et al., 2011). In these models, cells may respond directly to a chemotactic signal or receive guidance from neighboring cells. As long-distance cell migration is a major aspect of embryonic development (Dormann and Weijer, 2003; Richardson and Lehmann, 2010; Tarbashevich and Raz, 2010; Kulesa and Gammill, 2010), adult morphogenesis (Hatten and Roussel, 2011), tissue repair (Burns and Steinberg, 2011) and cancer metastasis (Roussos et al., 2011; Friedl and Gilmour, 2009), the examination of this phenomenon could have significant implications for better understanding birth defects and disease. Yet, even with multiscale data collected from different model systems and emerging computational models, the cellular and molecular mechanisms of long distance cell migration are still unclear. This is due in part to a disconnect between theory and experiment that limits the testing of various hypotheses parametrised by biological data. Thus, what is needed is a fully integrative experimental-modeling approach that can reject certain hypotheses in favor of others and elucidate multiscale mechanisms of cell migration. Here, we examine how a subpopulation of embryonic cells travel long distances and respond to tissue growth to accurately reach a target. We study this question using the neural crest (NC) as our model experimental system. NC cells exit the dorsal neural tube (NT) and travel long distances throughout the developing embryo along stereotypical pathways rich in microenvironmental signals, mesoderm and extracellular matrix (Noden and Trainor, 2005; Perris and Perissinotto, 2000). The NC cell population is crucial for proper development of the face, heart and peripheral nervous systems, and is the cellular origin of the highly aggressive cancers, melanoma and neuroblastoma (Trainor, 2005; Sauka-Spengler and Bronner-Fraser, 2008; Gammill and Roffers-Agarwal, 2010; Kasemeier-Kulesa et al., 2008; Jiang et al., 2011). The recent explosion of multiscale cellular and molecular data on NC cell migration (Kulesa et al., 2010; Kulesa and Gammill, 2010; 1Stowers Institute for Medical Research, 1000 East 50th St, Kansas City, MO 64110, USA. 2Oxford University, Centre for Mathematical Biology, Mathematical Institute, University of Oxford, 24-29 St Giles’, Oxford OX1 3LB, UK. 3Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. 4Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 64157, USA.