Molecular Mechanisms of Cell Segregation and Boundary Formation in Development and Tumorigenesis

Abstract

SUMMARYThe establishment and maintenance of precisely organized tissues requires the formation of sharp borders between distinct cell populations. The maintenance of segregated cell populations is also required for tissue homeostasis in the adult, and deficiencies in segregation underlie the metastatic spreading of tumor cells. Three classes of mechanisms that underlie cell segregation and border formation have been uncovered. The first involves differences in cadherin-mediated cell -cell adhesion that establishes interfacial tension at the border between distinct cell populations. A second mechanism involves the induction of actomyosin-mediated contraction by intercellular signaling, such that cortical tension is generated at the border. Third, activation of Eph receptors and ephrins can lead to both decreased adhesion by triggering cleavage of E-cadherin, and to repulsion of cells by regulation of the actin cytoskeleton, thus preventing intermingling between cell populations. These mechanisms play crucial roles at distinct boundaries during development, and alterations in cadherin or Eph/ephrin expression have been implicated in tumor metastasis.

Eph/ephrin signalling during development

“…Complementary expression of ephrin B and EphB is sufficient to segregate intermingled cells and is required to maintain sharp borders (Batlle and Wilkinson, 2012). Such reciprocal expression of Eph and ephrin proteins occurs in many tissues during development -most notably in hindbrain rhombomeres and somites -and underlies cell segregation.…”

“…Cell positioning along the crypt-villus axis of the small intestine is controlled by EphB/ephrin B interactions between epithelial cells (Batlle and Wilkinson, 2012). In newborn mice, EphB2 and EphB3 are expressed in the intervillus pockets, whereas ephrin B1 distribution is complementary to EphB proteins, being excluded from the bottom-most cells.…”

A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary

“…The links between cell fate determination and the physical mechanisms guiding cell separation, however, remain unknown. A feature of many developing tissues is the separation of cells with distinct fates or functions into compartments (Vincent, 1998;McNeill, 2000;Irvine and Rauskolb, 2001;Tepass et al, 2002;Blair, 2003;Vincent and Irons, 2009;Martin and Wieschaus, 2010;Dahmann et al, 2011;Monier et al, 2011;Batlle and Wilkinson, 2012). Boundaries between compartments are characterized by a straight morphology.…”

The cellular basis of tissue separation

“…One of the fundamental concepts of morphogenesis is tissue separation (see Glossary Box 1): the process that physically segregates two cell populations (Batlle and Wilkinson, 2012;Dahmann et al, 2011;Tepass et al, 2002;Wacker et al, 2000;Winklbauer, 2009). This process is essential to maintain the coherence of embryonic tissues despite the strong propensity of cells to mix, as augmented by extensive cell division and migration during development.…”