The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within tissues remains largely unknown. Here, using a zebrafish model, we show that the nucleus, the biggest cellular organelle, functions as an elastic deformation gauge that enables cells to measure cell shape deformations. Inner nuclear membrane unfolding upon nucleus stretching provides physical information on cellular shape changes and adaptively activates a calcium-dependent mechanotransduction pathway, controlling actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behavior to their microenvironment.

Errors in early embryogenesis are a cause of sporadic cell death and developmental failure1,2. Phagocytic activity has a central role in scavenging apoptotic cells in differentiated tissues3,4,5,6. However, how apoptotic cells are cleared in the blastula embryo in the absence of specialized immune cells remains unknown. Here we show that the surface epithelium of zebrafish and mouse embryos, which is the first tissue formed during vertebrate development, performs efficient phagocytic clearance of apoptotic cells through phosphatidylserine-mediated target recognition. Quantitative four-dimensional in vivo imaging analyses reveal a collective epithelial clearance mechanism that is based on mechanical cooperation by two types of Rac1-dependent basal epithelial protrusions. The first type of protrusion, phagocytic cups, mediates apoptotic target uptake. The second, a previously undescribed type of fast and extended actin-based protrusion that we call 'epithelial arms', promotes the rapid dispersal of apoptotic targets through Arp2/3dependent mechanical pushing. On the basis of experimental data and modelling, we show that mechanical load-sharing enables the long-range cooperative uptake of apoptotic cells by multiple epithelial cells. This optimizes the efficiency of tissue clearance by extending the limited spatial exploration range and local uptake capacity of non-motile epithelial cells. Our findings show that epithelial tissue clearance facilitates error correction that is relevant to the developmental robustness and survival of the embryo, revealing the presence of an innate immune function in the earliest stages of embryonic development. Main textEarly embryogenesis is prone to cellular errors like mitotic defects induced by cell intrinsic or extrinsic stress factors1,2. This leads to sporadic cell death of progenitor stem cells3-6, assumed to be a major cause of early developmental failures in human pre-implantation development7,8. Stochastic cell death is expected to occur at random locations, vary in cell number and differ from developmentally programmed cell death occurring at later stages in vertebrate embryogenesis, which has predefined spatiotemporal dynamics and specific functions in morphogenetic processes9. Detection and removal of cell corpses requires specific clearance mechanisms as mediated by professional phagocytic cells in adult tissues10. Whether such active mechanisms for efficient apoptotic tissue clearance exist in early blastula and gastrula

The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical 20 stress and physical space constraints within their local environment remains largely unknown. Here we show that the nucleus, the biggest cellular organelle, functions as a non-dissipative cellular shape deformation gauge that enables cells to continuously measure shape variations on the time scale of seconds. Inner nuclear membrane unfolding together with the relative spatial intracellular positioning of the nucleus provides physical information on the amplitude and type 25 of cellular shape deformation. This adaptively activates a calcium-dependent mechanotransduction pathway, controlling the level of actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behaviour to their microenvironment. 30 One Sentence Summary: The nucleus functions as an active deformation sensor that enables cells to adapt their behavior to the tissue microenvironment.Main Text: The 3D shape of an organism is built by active force-generating processes at the cellular level and the spatio-temporal coordination of morphodynamic cell behavior. Contractility 35 of the acto-myosin cell cortex represents a major cellular force production mechanism underlying cellular shape change (1), cell polarization (2) and active cell migration dynamics (3). Contractility levels are regulated by the activity of non-muscle myosin II motor proteins (4) and are spatiotemporally controlled to tune single cell and tissue morphodynamics during development (5, 6) and tissue homeostasis and disease in the adult organism (7,8). Still, mechanisms that regulate the 40 set point level of cortical contractility on the single cell level remain poorly understood.