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.

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.

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