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Mechanical forces exerted on neural crest cells control their collective migration and differentiation. This perspective discusses our current understanding of neural crest mechanotransduction during cell migration and differentiation. Additionally, we describe proteins that have mechanosensitive functions in other systems, such as mechanosensitive G-protein-coupled receptors, mechanosensitive ion channels, cell-cell adhesion, and cell-matrix-interacting proteins, and highlight that these same proteins have in the past been studied in neural crest development from a purely signaling point of view. We propose that future studies elucidate the mechanosensitive functions these receptors may play in neural crest development and integrate this with their known molecular role.
Figure 1. Effect of mechanical forces on neural crest cells
(A) (A and A′) Illustration of sagittal sections of Xenopus laevis embryos at a non-migratory NC stage (stage 13) (A) and at the onset of NC cell migration (stage 20) (A′). As the mesoderm proliferates during embryonic development, the apparent elasticity of the tissue increases. Non-migratory NC cells adjacent to the mesoderm sense the increase in mesoderm stiffness through focal adhesion (FA) proteins, which triggers EMT and NC collective migration.
(B) Additionally, migratory neural crest cells sense a stiffness gradient across the placode tissue and direct their migration via durotaxis (B) neural crest stem cells (NCSCs) derived from induced pluripotent stem cells (iPSCs) cultured on gels of different stiffness undergo specific cell differentiation patterns. NCSCs cultured on stiff gels (1 GPa) differentiate into smooth muscle cells after 3 days. NCSCs cultured on soft gels (15 kPa) differentiate into Schwann glial cells after 3 days.
Figure 2. Cell membrane mechanosensors expressed by neural crest cells
(A) Illustration of two migratory neural crest (NC) cells which are forming cell-cell and cell-matrix contacts. Each mechanosensor is specified by a red star and a number, which are described in more detail in (B–E).
(B) Mechanosensitive G-protein-coupled receptors (GPCRs). Upon mechanical activation, GPCRs activate phospholipase C (PLC) signaling. PLC mediates (1) the conversion of IP2 to IP3, which can activate mechanosensitive ion channels and lead to increased Ca2+ levels, and (2) the conversion of IP2 into membrane-bound diacylglycerol (DAG), which activates proteinase kinase C (PKC), and signaling downstream of this enzyme.
(C) Mechanosensitive (MS) ion channels. Mechanical activation of TRP and Piezo1 channels allows entry of Ca2+ and Mg2+ ions and the activation of signaling Ca2+/Mg2+-dependent signaling pathways.
(D) Cadherin-based cell-cell adhesions. Cell membrane tension by intrinsic actomyosin contractility or extracellular forces can be detected by cadherin-based junctions, which leads to actin remodeling via α-catenin unfolding and/or vinculin recruitment.
(E) Integrin-focal adhesion complex. Forces exerted by the extracellular matrix are sensed by integrin proteins and propagated by focal adhesions (FA). Mechanotransduction via FA proteins leads to (1) the recruitment of signaling kinases (Src and FAK), (2) modification of stress fibers via vinculin binding, and (3) small GTPase activation through guanosine exchange factors (GEFs).
