Evolve stage 2 rotation9/12/2023 (C) The inversion is an angular movement of at least 90°. Sibling hair cells undergo positional inversion to place Notch-on/Emx2(−) and Notch-on/Emx2(+) cells on opposite sides of the epithelium. Unipotent progenitors (UHCP) divide into two hair cells. Dashed line indicates the midline of the organ. (A) Scheme of a neuromast, depicting an outer ring of mantle cells (red), internal supporting cells (gray) and central hair cells (light blue) with their axis of planar polarity (dark blue dots). Inversions are local movements of nascent sibling hair cells. Concurrently with this step, around half of the hair-cell pairs rotate once around their geometric center ( Fig. 1B-D and Movie 1) ( Wibowo et al., 2011 Mirkovic et al., 2012). Although this symmetry-breaking process is deterministic in that it always results in one of the siblings losing Emx2 expression, it is also stochastic because it is unpredictable which cell will do so. The cell that activates the Notch1a receptor (Notch-on) loses Emx2 expression, whereas its sibling (Notch-off) maintains it. Local lateral-inhibitory signaling via Notch1a breaks the initial symmetry in nascent sibling hair cells by repressing the transcription factor Emx2 in one of them ( Jacobo et al., 2019 Kozak et al., 2020). During turnover, hair cells are produced sequentially, in pairs or dyads, from the mitotic division of facultative unipotent progenitors (UHCP) that originate from internal supporting cells ( López-Schier and Hudspeth, 2006 Ma et al., 2008 Cruz et al., 2015 Denans et al., 2019 Thomas and Raible, 2019 Hardy et al., 2021 Baek et al., 2022). Hair cells undergo continuous renewal without modifying the architecture of the organ ( Cruz et al., 2015 Pinto-Teixeira et al., 2015 Peloggia et al., 2021). Hair cells are also polarized along a single axis across the apical face of the epithelium ( López-Schier and Hudspeth, 2006). They consist of a radial-symmetric epithelium containing mechanosensory hair cells in the center, and two types of non-sensory supporting cells forming two outward concentric rings ( Fig. 1A) ( Wada and Kawakami, 2015). Neuromasts display largely invariant size and pattern. Here, we focus on a minimal model of collective cell rotations involving the positional inversion of just two cells, which was first described in neuromasts of the zebrafish lateral line ( Wibowo et al., 2011). Aided by computer modeling, we suggest that initial stochastic inhomogeneities generate a metastable state that poises cells to move and spontaneous intercellular coordination of the resulting instabilities enables persistently directional rotations, whereas Notch1a-determined symmetry breaking buffers rotational noise. Moreover, the Notch/Emx2 status of the cell dyad does not determine asymmetric interactions with the surrounding epithelium. We found no correlation between rotations and epithelium-wide cellular flow or anisotropic resistive forces. Here, we show that this multicellular rotation is a three-phasic movement that progresses via coherent homotypic coupling and heterotypic junction remodeling. In zebrafish neuromasts, nascent sibling hair cells invert positions by rotating ≤180° around their geometric center after acquiring different identities via Notch1a-mediated asymmetric repression of Emx2. However, it is unclear whether this notion can be extrapolated to a natural context, where rotations are ephemeral and heterogeneous cellular cohorts interact with an active epithelium. Theoretical and in vitro studies have conceptualized rotating cells as identical rigid-point objects that stochastically break symmetry to move monotonously and perpetually within an inert environment. Collective cell rotations are widely used during animal organogenesis.
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