The road best traveled: Neural crest migration upon the extracellular matrix

Abstract

Neural crest cells have the extraordinary task of building much of the vertebrate body plan, including the craniofacial cartilage and skeleton, melanocytes, portions of the heart, and the peripheral nervous system. To execute these developmental programs, stationary premigratory neural crest cells first acquire the capacity to migrate through an extensive process known as the epithelial-to-mesenchymal transition. Once motile, neural crest cells must traverse a complex environment consisting of other cells and the protein-rich extracellular matrix in order to get to their final destinations. Herein, we will highlight some of the main molecular machinery that allow neural crest cells to first exit the neuroepithelium and then later successfully navigate this intricate in vivo milieu. Collectively, these extracellular and intracellular factors mediate the appropriate migration of neural crest cells and allow for the proper development of the vertebrate embryo.

Keywords: Epithelial-to-mesenchymal transition; Extracellular matrix; Migration; Neural crest cells.

Figure 1.. General overview of the neural crest, including target tissues and derivatives as well as EMT.

A. A vertebrate embryo with migratory neural crest cells depicted in orange (arrows indicate direction of migration). Neural crest cells that delaminate from the cranial neural tube region (green) differentiate into bone and cartilage cells of the craniofacial skeleton, sensory neurons and glia of the cranial ganglia, and melanocytes. Neural crest cells from the vagal region of the neural tube (yellow) contribute to cardiac muscle, sympathetic and parasympathetic ganglia, and the enteric (gut) nervous system. Neural crest cells from the trunk region (gray) form neurons and glia of dorsal root ganglia, sympathetic ganglia, and chromaffin cells of the adrenal medulla. Not pictured are neural crest cells from the sacral, or most caudal, region of the neural tube, which gives rise to enteric and sympathetic ganglia. B. A representative image of cranial neural crest cells (orange), which originate in the dorsal neural tube, before (left) and after (right) the start of EMT. Before EMT, the basement membrane (red), composed of laminin, fibronectin, and collagens, is a barrier to neural crest emigration. During EMT, neural crest cells and surrounding tissues secrete several proteases (represented as scissors) of the MMP and ADAM families, which help degrade the basement membrane and process cell surface cadherins. C. A higher magnification of the boxed area in (B). Neural crest cells undergoing EMT secrete proteases into the extracellular space to promote EMT. Epithelial-like premigratory neural crest cells within the dorsal neural tube form junctions with neighboring cells through the expression of type 1 (green lines) and type II (blue lines) cadherins. Migratory neural crest cells become polarized through the planar cell polarity pathway, expressing Rac GTPases at the leading edge (yellow) and Rho GTPases at the trailing edge (red), which regulate the actin cytoskeleton to enable directional movement. Proteases in the extracellular space degrade basement membrane ECM (red), while also cleaving cadherins. Resulting extracellular fragments increase activity of proteases, providing a positive feedback loop to further enhance EMT.

Figure 2.. Molecular interactions between migratory neural crest and ECM.

A. Diagram of collectively migrating neural crest cells (orange). Neural crest cells migrate upon permissive ECM substrates (green), including fibronectin and laminin, while avoiding inhibitory ECM substrates (purple) such as aggrecan and versican. Migratory cells are polarized, with distinct leading (yellow) and trailing (red) edges. Orange arrow indicates direction of migration. B. A higher magnification view of (A) to illustrate molecular and cellular changes occurring during migration. At the leading edge of migrating neural crest cells, integrins form focal adhesions with the ECM under lamellipodia, tethering the extracellular environment to the actin cytoskeleton (1). Cell contacts are maintained by cell adhesion molecules like Cadherin-11 during migration (2), and confinement of migrating streams by versican (3) enhances directional migration. Rac GTPase activation at the leading edge promotes actin polymerization (4), while Rho GTPase activation causes actin depolymerization at the trailing edge. Migrating neural crest cells are guided by diffusible signals (blue circles), including Sdf-1, whose local concentrations may be influenced by the ECM. Integrins also bind to growth factor receptors and other cell surface molecules to integrate signals from the extracellular environment (5).