D’Arcy Thompson predicted a century ago that animal body shape is conditioned by gravity, but there has been no animal model to study how cellular forces are coordinated to generate body shapes that withstand gravity; the hirame medaka fish mutant, with pronounced body flattening, reveals how the hirame/YAP gene controls gravity-resisting cellular forces to produce complex 3D organs and body shapes. How is tissue tension controlled at the organismal level to maintain body shape and complex three-dimensional structures? Makoto Furutani-Seiki and colleagues describe a medaka fish mutant, hirame (hir), with a flattened body. They show that the phenotype is due to reduction of internal forces caused by the absence of YAP protein, part of the Hippo signalling pathway. This striking effect is linked to the control exerted by YAP on actomyosin-mediated tension through the regulation of the RhoGAP GTPase activating protein ARHGAP18. YAP also controls the 3D structure of human cell spheres in this manner in a human cell culture system. Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head1. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force2,3. Although a century ago D’Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity4, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues.

Group B1 Sox genes encode HMG domain transcription factors that play major roles in neural development. We have identified six zebrafish B1 sox genes, which include pan‐vertebrate sox1a/b, sox2, and sox3, and also fish‐specific sox19a/b. SOX19A/B proteins show a transcriptional activation potential that is similar to other B1 SOX proteins. The expression of sox19a and sox3 begins at approximately the 1,000‐cell stage during embryogenesis and becomes confined to the future ectoderm by the shield stage. This is reminiscent of the epiblastic expression of Sox2 and/or Sox3 in amniotes. As development progresses, these six B1 sox genes display unique expression patterns that overlap distinctly from one region to another. sox19a expression is widespread in the early neuroectoderm, resembling pan‐neural Sox2 expression in amniotes, whereas zebrafish sox2 shows anterior‐restricted expression. Comparative genomics suggests that sox19a/b and mammalian Sox15 (group G) have an orthologous relationship and that the B1/G Sox genes arose from a common ancestral gene through two rounds of genome duplication. It seems likely, therefore, that each B1/G Sox gene has gained a distinct expression profile and function during vertebrate evolution. Developmental Dynamics 235:811–825, 2006.

MHC class I-related protein 1 (MR1) is a metabolite-presenting molecule that restricts MR1-reactive T cells including mucosal-associated invariant T (MAIT) cells. In contrast to MAIT cells, the function of other MR1-restricted T cell subsets is largely unknown. Here, we report that mice in which a T cell-specific transcription factor, B-cell lymphoma/leukemia 11B (Bcl11b), was ablated in immature thymocytes (Bcl11b^∆iThy mice) develop chronic inflammation. Bcl11b^∆iThy mice lack conventional T cells and MAIT cells, whereas CD4⁺IL-18R⁺ αβ T cells expressing skewed Traj33 (Jα33)⁺ T cell receptors (TCR) accumulate in the periphery, which are necessary and sufficient for the pathogenesis. The disorders observed in Bcl11b^∆iThy mice are ameliorated by MR1-deficiency, transfer of conventional T cells, or germ-free conditions. We further show the crystal structure of the TCR expressed by Traj33⁺ T cells expanded in Bcl11b^∆iThy mice. Overall, we establish that MR1-reactive T cells have pathogenic potential.