Polarity and migration of cranial and cardiac neural crest cells: underlying molecular mechanisms and disease implications

Abstract

The Neural Crest cells are multipotent progenitor cells formed at the neural plate border that differentiate and give rise to a wide range of cell types and organs. Directional migration of NC cells and their correct positioning at target sites are essential during embryonic development, and defects in these processes results in congenital diseases. The NC migration begins with the epithelial-mesenchymal transition and extracellular matrix remodeling. The main cellular mechanisms that sustain this migration include contact inhibition of locomotion, co-attraction, chemotaxis and mechanical cues from the surrounding environment, all regulated by proteins that orchestrate cell polarity and motility. In this review we highlight the molecular mechanisms involved in neural crest cell migration and polarity, focusing on the role of small GTPases, Heterotrimeric G proteins and planar cell polarity complex. Here, we also discuss different congenital diseases caused by altered NC cell migration.

Keywords: cell migration; cell polarity; cell signaling; neural crest (NC); neural crest disorder.

FIGURE 1

Cellular and Molecular mechanisms regulating Neural Crest (NC) cell migration and polarity. (A) Schematic representation of a group of collectively migrating NC cells with polarized leader cells at the forefront. The in vivo migration routes are delineated by confinement boundaries expressing different members of the ephrin/Eph family. A highlighted box indicates two of the leader cells in the group, expanded in (B, C). (B) Enlarged view of the leader cells showing the antagonistic regulation of RhoA and Rac1. RhoA facilitates cellular retraction at the posterior edge, while Rac1 promotes protrusions at the anterior edge. Rac1 activity is modulated by several pathways including Trio and Cdc42. The CXCR4/Sdf1 signaling pathway, originating from placodal cells, guides the migratory trajectories of NC cells. Meanwhile, C3a signaling, released by the NC cells themselves, helps maintain their cohesion through a mechanism of co-attraction by regulating Rac1 activity. Contact Inhibition of Locomotion (CIL) is driven by Rac1 inhibition at the cell-cell contacts. This process is intricately regulated by the activation of Ric8A, which activates Gα proteins. Then Gα proteins activates Par3 that inhibits Trio at cell-cell contacts, leading to a specific localized Rac1 inhibition and ensuring proper cell retraction. (C) Planar Cell Polarity (PCP) at the leading edge is regulated by the WNT signaling pathway, which activates Frizzled receptors. This, in turn, activate Dishevelled (Dsh/Dvl) and PTK7, leading to the downstream activation of RhoA. RhoA inhibits Trio and Rac1 to ensure proper cell polarity. Calponin-2 (Cnn2) at the leading edge induces protrusion formation necessary for cell migration. This regulation is crucial for maintaining the balance between cell protrusion and retraction, enabling directed migration.

FIGURE 2

Neural Crest (NC) cell Migration in response to mechanical cues. (A) NC cells exhibiting collective migration in response to durotactic signals, characterized by a gradient of extracellular matrix (ECM) stiffness due to ECM composition, and cell density in the mesodermal tissue. This process involves integrin-mediated signaling and focal adhesion formation, leading to Rac1 activation and subsequently, actin polymerization and protrusion formation at the leading edge, while RhoA activation inhibit protrusion formation via Contact Inhibition of Locomotion (CIL). The mechanical properties of the ECM and mesodermal stiffness play crucial roles in guiding the directional migration of NC cells. (B) At low cell density, NC cells switch to an amoeboid-like migration, characterized by less dependence on focal adhesions and integrin signaling. Instead, this mode relies on the flexibility of the cell cortex and actomyosin contractility, allowing cells to move through the ECM with increased plasticity and adaptability. Amoeboid migration is facilitated by changes in cell shape and rapid, transient protrusions, enabling efficient navigation through variable ECM environments.