How is tubulogenesis regulated by mechanics?

The basic steps during tube formation, including cell polarization, the formation of small multiple lumens and the coalescence of multiple lumens into a single lumen, and subsequent tube elongation, are directly regulated by mechanical signals arising from neighbouring cells as well as the extracellular matrix.  Here, we briefly discuss the underlying principles in the mechano-regulation of tubulogenesis.

Cell polarization, a prerequisite for tube formation, involves a series of well-coordinated processes such as polarization of the cytoskeletal networks, including the actin filaments and the microtubules, polarized vesicular transport, as well as the assembly of multi-protein complexes on the plasma membrane, including cell-cell junctional and polarity complexes, which specify distinct subdomains within the plasma membrane [1][2][3].  The physical linkages of the cytoskeletal structures with cell-cell or cell-matrix adhesions provide a basis for the regulation of cell polarization by mechanical signals arising from the cellular microenvironment. The mechanical cues may influence epithelial remodeling via collective cell migration and apoptosis to form multiple small lumens as well as regulate the paracellular and transcellular transport of fluids via tight junctions, which would drive the coalescence of small lumens into a single, continuous lumen [4].

Studying the formation of gut in Zebrafish, Stainier et al. showed that a defect in atypical protein kinase C, a polarity complex component, resulted in multiple lumen defects, which highlighted the significance of proper apico-basal polarization of cells during gut morphogenesis [5][6][4]. In a more recent study, the group identified a role for claudin-15, a tight junction component, in specifying single lumen morphology [4]. Using in-situ hybridization tests, the study confirmed that claudin-15 expression in the gut is under the control of Tcf2 (a transcription factor 2 that drives endoderm differentiation in mammals and fish), as mutations in Tcf2 led to a marked down regulation of claudin-15 expression. However, Tcf2 mutations and down-regulated claudin-15 expressions were found to have no effects on the assembly of tight junctions and on the barrier functions mediated by these junctional complexes. Instead, the formation of ion-permeable pores by claudin-15 was found to be greatly compromised in Tcf-2 mutants. In wild-type intestinal epithelial cells, claudin-15 forms ion-permeable pores that allows the movement of ions and fluid across the epithelium into the intestinal lumen. The forces generated due to the accumulation of fluid drives the coalescence of multiple small lumens into a single, continuous lumen. A disruption to the paracellular and transcellular transport of fluids in claudin-15-deficient cells would explain the lack of sufficient forces to drive luminal expansion, leading to multiple lumen phenotype in these cells [4]. In conjunction with the role of cell-cell junctions in driving the hydrostatic expansion of lumens, a recent study shows how the spatial organization of the extracellular matrix around cells can also direct lumen elongation by inducing anisotropic intercellular mechanical tension. The ECM-induced stress separates adjacent membranes and further elongates lumens in the direction of minimal tension, reflecting a direct role of mechanical forces during tube formation [7].

The initial steps in tube formation are followed by cellular events such as shape changes, divisions, and rearrangements, which drive the growth and elongation of tubes. Each of these processes involve remodeling of the cytoskeleton and are directly regulated by mechano-signaling pathways mediated via focal adhesions as well as adherens junctions [8]. For instance, alpha-catenin, a key adherens junctions component that links the membrane-bound E-cadherin with the cortical actin network, has been proposed to relay mechanical signals essential for lumen elongation [9]. Furthermore, the changes to cell shape during both wrapping and budding are primarily driven by apical constriction, an actomyosin-mediated process that causes polarized epithelial cells to migrate to the point of invagination, contract along the top-bottom axis, as the epithelium gets remodeled into tubular structures. In vertebrates and Drosophila, localized activation of Rho kinases at the apical surfaces of cells results in the activation and accumulation of non-muscle myosin II at these sites. In vertebrates, there is a simultaneous recruitment of F-actin mediated by Abelson tyrosine kinase signaling pathways. The myosin and the F-actin organize into a continuous contractile network that is tethered to adherens junctions on lateral cell surfaces. The purse-string like contractions of this actomyosin network has for long been proposed to drive apical constrictions [10]. However, recent live imaging using Drosophila embryos have proposed a ratcheting mechanism, in which repeated myosin contractions at the medial apical region would pull the adherens junctions inwards, thereby reducing the apical surface area of the cell [11].

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