2026/02/01 by Wade W. Sugden, Brian A. Link · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Hippo pathway signaling and YAP/TAZ #Cellular Mechanics and Interactions #Axon Guidance and Neuronal Signaling
paper · doi:10.1242/dev.205506
openalex publication_date 2026/02/01 · openalex created_date 2026/02/04 · openalex updated_date 2026/07/31
During development, as well as regeneration, cells respond to their environment to facilitate tissue morphogenesis. Among the multitude of cues in the cellular microenvironment are biomechanical properties, including shear stress, tensile force, extracellular matrix stiffness-elasticity, fluid viscosity and other external features that are transduced into signaling cascades that modulate the cytoskeleton and regulate gene expression.Understanding of cellular mechanotransduction has grown over the past decade, not only in development and regeneration, but also during tissue homeostasis and in disease (Di et al., 2023). There has been significant progress on characterizing the transmembrane proteins that can directly sense mechanical force and properties. Mechanosensitive proteins include a variety of ion channels, G-protein coupled receptors, integrins, cell adhesion molecules, among others (Goodman et al., 2023). These couple to distinct signaling cascades.The homologous transcriptional regulators YAP and TAZ have emerged as important integrators of biomechanical influences (Cobbaut et al., 2020; Elbediwy and Thompson, 2018). A key feature of YAP and TAZ is the exquisite ‘context-sensitive’ nature of their functional outputs. This includes documented roles in differentiation and stem cell maintenance, growth versus apoptosis, and defining the redundant and unique YAP/TAZ roles in specific cell types (LeBlanc et al., 2021). This diversity of outcomes can stem from differential expression of YAP and TAZ themselves, or by the cellular milieu of DNA binding factors that can direct YAP/TAZ gene regulation (Kim et al., 2018).Given the inherent complexity of YAP/TAZ signaling, important questions remain on the precise regulatory controls and feedback responses that coordinate changes to external biomechanical properties with the intrinsic cell responses in any specific system. Three recent preprints, overviewed below, address the upstream and downstream mechanisms of YAP/TAZ-mediated mechanotransduction in different tissue (re)generation contexts (Ferreira et al., 2025 preprint; Kurup et al., 2025 preprint; Mori et al., 2025a preprint).The semi-circular canals of the inner ear are fluid-filled, looped tubes that mediate vestibular functions. These structures derive from the otic vesicle epithelium through three general processes: bud initiation, extension and fusion (Mackowetzky et al., 2021).In their preprint, Mori et al. leverage the zebrafish model to investigate whether mechanotransduction feedback signaling might drive semi-circular canal morphogenesis (Mori et al., 2025a preprint). Previous studies have demonstrated that localized hyaluronan and versican synthesis, mediated by Lmx1b transcriptional activity, promotes ECM swelling and results in osmotic pressure to trigger bud initiation (Mori et al., 2025b; Munjal et al., 2021). Asymmetrically distributed actomyosin-rich membrane tethers termed cytocinches provide resistance to osmotic pressure driving longitudinal growth of the buds. How semi-circular canal structures maintain extension and then extinguish growth remained unknown.Based on the established role of Yap as a mechanoresponsive transcription factor, Mori and colleagues generated a transgenic reporter that fused a fluorescent protein to endogenously expressed Yap. Yap was found within the nucleus in the budding epithelium, but was absent at the pre-bud stage. Yap activation in the extending buds depended on osmotic pressure, as hyaluronidase treatment resulted in loss of nuclear Yap and importantly, reduced bud extension. Similarly, direct knockdown of yap1 inhibited bud elongation. Single-cell transcriptomic atlases were used to identify a cellular communication network (CCN) matricellular modulating family member, ccn1l1, as a candidate Yap target gene. Deleting Yap confirmed this notion. Interestingly, ccn1l1 knockdown reduced factors responsible for synthesizing hyaluronan and versican, suggesting a positive feedback loop where osmic pressure from ECM activates Yap which drives Ccn1l1 resulting in more ECM swelling.To address how this self-amplifying system is spatially patterned, the investigators leveraged theoretical modeling, which indicated that mechanical stress might be concentrated at cells bordering the bud. Indeed, indicators of mechanical stress – nuclear aspect ratios and Yap activity – supported this prediction. Feedback loop termination was found to depend on the mechanosensitive adhesion-type G-protein-coupled receptor, Gpr126. Published work has shown that in gpr126 mutants, buds fail to fuse and show excessive elongation (Geng et al., 2013). Mori et al. extended this observation by showing Gpr126 terminates ccn1l1 expression via regulating cAMP responsive element binding protein (CREB) transcriptional activity, which has been reported to downregulate CCN family genes.While key questions remain, including precisely how osmotic pressure activates Yap and what triggers Gpr126 activity with bud fusion, data in this preprint contributes to closing the loop on understanding how semi-circular canals form.The zebrafish lateral line (LL) is a system in which a primordium of neuronal cells migrates from head to tail over 3 days of development, sequentially depositing rosettes of neuromasts that enable the animal to detect motion while swimming. The superficial localization of the LL allows for high-resolution study of the 4-dimensional kinetics of this process, including the interplay of signaling pathways, environmental cues and cell-cell interactions in morphogenesis (Nogare et al., 2017).A new preprint by Kurup, Mikdache and colleagues identifies Sox2 as a neural-specific transcription factor that controls the precise size, timing and location of neuromast deposition, in part by tuning mechanical feedback activity of YAP/TAZ (Kurup et al., 2025 preprint). This expands on earlier work showing that YAP can control cell number and size of neuromasts (Agarwala et al., 2015).While previous studies have implicated a relationship between cell number and deposition rate of neuromasts (Valdivia et al., 2011), Kurup, Mikdache et al. show here by thorough gain- and loss-of-function genetics of both sox2/sox3 and yap/taz genes that cell number in neuromasts is negatively regulated by sox2, and that the increased number and proliferation of cells in sox2−/− is due to mechanically-stimulated YAP/TAZ signaling. A combination of chemical and physical approaches shows that tensional forces generated by proliferating cells in the primordia serve as the mechanical cue for YAP/TAZ activity. Laser ablation of junctions shows reduced tension in the context of hydroxyurea-stunted cell proliferation, and this is coupled with less ctgfa:GFP (YAP-responsive) reporter readout. Actin-disrupting drugs and expression of active/dominant-negative RhoA recapitulate YAP gain/loss-of-function phenotypes, and yap1−/− normalizes the sox2−/− phenotype of supernumerary cells and earlier deposition of neuromasts.While direct measurement of endogenous YAP localization was not performed, this is the only one of the three preprints reviewed here to systematically investigate the combined effects of both YAP and TAZ genes on the mechanosensitive process of LL development, and also highlights how a lineage-specific TF, sox2, controls the cellular parameter of proliferation to generate a YAP/TAZ activating cue.Regeneration is a unique form of morphogenesis which can re-enlist developmental pathways and/or deploy regeneration-specific gene regulatory modules (Poss and Tanaka, 2024). A preprint by Ferreira et al. shows that a biomechanical feedback loop driven by YAP is essential for maintaining tailbud regeneration in Xenopus laevis (Ferreira et al., 2025 preprint).Tadpoles of this amphibian completely regenerate amputated tails within 7 days. Using atomic force microscopy to probe the mechanical properties of this tissue, the authors show that the regenerative bud rapidly increases in stiffness following amputation, a prospective mechanical signal that might stimulate outgrowth. Indeed, increased YAP nuclear activity is positively correlated with tail bud stiffness and reducing this stiffness by tissue ablation or disruption of actin polymerization led to failed outgrowth.The authors identify the mechanically-gated ion channel Piezo1 as responsible for activating YAP, as has been shown in other contexts (Duchemin et al., 2019; Zhou et al., 2020). Elegant epistasis experiments with chemical agonists/antagonists for both Piezo1 and YAP demonstrate that YAP is required for Piezo1-dependent regeneration, and that YAP function is essential during early bud formation and growth, but dispensable later. This highlights that YAP-driven biomechanical feedback often integrates with other genetic processes to help specialized tissues complete morphogenesis. A key finding made possible by the unique Xenopus model is that chemical activation of Piezo1 and the subsequent YAP activity is sufficient to enable regeneration during a larval stage in which this capability is not normally present.Whether Piezo1/YAP is required for normal tail development, or what factors contribute to increased tissue stiffness to set off regeneration, is not addressed, but the findings reported in this preprint provide a roadmap for stimulating the Piezo1/YAP axis in other (re)generative contexts.Collectively, the strength of the rigor and similar findings in three separate, but related, biological systems suggests that mechanotransduction feedback loops are central to the organized construction of tissues from (re)generative primordia of cells. In these three preprints specifically, an external physical cue (ECM swelling, proliferative cell-tension or wound stiffness) activates YAP/TAZ to control the proper morphogenesis of ‘buds’ of cells in semi-circular canal (Mori et al., 2025a preprint), LL primordium (Kurup et al., 2025 preprint) and regenerating tail blastema (Ferreira et al., 2025 preprint). Notably, in each of these systems YAP/TAZ activity is not essential for the developmental appearance of the (re)generative-competent tissue per se, but is crucial for the dynamic completion of morphogenesis.It is therefore intriguing to speculate that YAP/TAZ mechanical modules are harnessed by newly-specified cells to overcome previous developmental states (implied in Kowalczyk et al., 2022) and form new structures without the need to genetically hardwire all possible new outcomes. Open questions remain for the field to consider on a case-by-case basis for any putative mechanically-sensitive morphogenetic process. Do YAP/TAZ function redundantly, and if so, which phenotypic elements relate to mechano-response and which to transcriptional programming? How do YAP/TAZ activities integrate with lineage-specific transcription factors to tune developmental morphogenesis by mechanical cues? Can the mechanisms described in these papers from aquatic vertebrates be applied in mammalian systems or human induced pluripotent stem cell models of tissue formation from ‘buds’ to reproduce desired (re)generation morphology and kinetics? The preprints highlighted here will no doubt inspire future studies to seek answers to these questions.