Mechanically guided cell fate determination in early development.

Cell fate determination, a vital process in early development and adulthood, has been the focal point of intensive investigation over the past decades. Its importance lies in its critical role in shaping various and diverse cell types during embryonic development and beyond. Exploration of cell fate determination started with molecular and genetic investigations unveiling central signaling pathways and molecular regulatory networks. The molecular studies into cell fate determination yielded an overwhelming amount of information invoking the notion of the complexity of cell fate determination. However, recent advances in the framework of biomechanics have introduced a paradigm shift in our understanding of this intricate process. The physical forces and biochemical interplay, known as mechanotransduction, have been identified as a pivotal drive influencing cell fate decisions. Certainly, the integration of biomechanics into the process of cell fate pushed our understanding of the developmental process and potentially holds promise for therapeutic applications. This integration was achieved by identifying physical forces like hydrostatic pressure, fluid dynamics, tissue stiffness, and topography, among others, and examining their interplay with biochemical signals. This review focuses on recent advances investigating the relationship between physical cues and biochemical signals that control cell fate determination during early embryonic development.

Competence for neural crest induction is controlled by hydrostatic pressure through Yap.

Embryonic induction is a key mechanism in development that corresponds to an interaction between a signalling and a responding tissue, causing a change in the direction of differentiation by the responding tissue. Considerable progress has been achieved in identifying inductive signals, yet how tissues control their responsiveness to these signals, known as competence, remains poorly understood. While the role of molecular signals in competence has been studied, how tissue mechanics influence competence remains unexplored. Here we investigate the role of hydrostatic pressure in controlling competence in neural crest cells, an embryonic cell population. We show that neural crest competence decreases concomitantly with an increase in the hydrostatic pressure of the blastocoel, an embryonic cavity in contact with the prospective neural crest. By manipulating hydrostatic pressure in vivo, we show that this increase leads to the inhibition of Yap signalling and impairs Wnt activation in the responding tissue, which would be required for neural crest induction. We further show that hydrostatic pressure controls neural crest induction in amphibian and mouse embryos and in human cells, suggesting a conserved mechanism across vertebrates. Our work sets out how tissue mechanics can interplay with signalling pathways to regulate embryonic competence.

RanBP1 plays an essential role in directed migration of neural crest cells during development.

Collective cell migration is essential for embryonic development, tissue regeneration and repair, and has been implicated in pathological conditions such as cancer metastasis. It is, in part, directed by external cues that promote front-to-rear polarity in individual cells. However, our understanding of the pathways that underpin the directional movement of cells in response to external cues remains incomplete. To examine this issue we made use of neural crest cells (NC), which migrate as a collective during development to generate vital structures including bones and cartilage. Using a candidate approach, we found an essential role for Ran-binding protein 1 (RanBP1), a key effector of the nucleocytoplasmic transport pathway, in enabling directed migration of these cells. Our results indicate that RanBP1 is required for establishing front-to-rear polarity, so that NCs are able to chemotax. Moreover, our work suggests that RanBP1 function in chemotaxis involves the polarity kinase LKB1/PAR4. We envisage that regulated nuclear export of LKB1 through Ran/RanBP1 is a key regulatory step required for establishing front-to-rear polarity and thus chemotaxis, during NC collective migration.