Shape-Tension Coupling Produces Nematic Order in an Epithelium Vertex Model.

We study the vertex model for epithelial tissue mechanics extended to include coupling between the cell shapes and tensions in cell-cell junctions. This coupling represents an active force which drives the system out of equilibrium and leads to the formation of nematic order interspersed with prominent, long-lived +1 defects. The defects in the nematic ordering are coupled to the shape of the cell tiling, affecting cell areas and coordinations. This intricate interplay between cell shape, size, and coordination provides a possible mechanism by which tissues could spontaneously develop long-range polarity through local mechanical forces without resorting to long-range chemical patterning.

A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice.

Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable or unpleasant sensations in the legs during rest periods. To relieve these sensations, patients move their legs, causing sleep disruption. While the pathogenesis of RLS has yet to be resolved, there is a strong genetic association with the MEIS1 gene. A missense variant in MEIS1 is enriched sevenfold in people with RLS compared to non-affected individuals. We generated a mouse line carrying this mutation (p.Arg272His/c.815G>A), referred to herein as Meis1R272H/R272H (Meis1 point mutation), to determine whether it would phenotypically resemble RLS. As women are more prone to RLS, driven partly by an increased risk of developing RLS during pregnancy, we focused on female homozygous mice. We evaluated RLS-related outcomes, particularly sensorimotor behavior and sleep, in young and aged mice. Compared to noncarrier littermates, homozygous mice displayed very few differences. Significant hyperactivity occurred before the lights-on (rest) period in aged female mice, reflecting the age-dependent incidence of RLS. Sensory experiments involving tactile feedback (rotarod, wheel running, and hotplate) were only marginally different. Overall, RLS-like phenomena were not recapitulated except for the increased wake activity prior to rest. This is likely due to the focus on young mice. Nevertheless, the Meis1R272H mouse line is a potentially useful RLS model, carrying a clinically relevant variant and showing an age-dependent phenotype.

Comparative Phenotyping of Mice Reveals Canonical and Noncanonical Physiological Functions of TRα and TRß.

Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRß1, and TRß2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRßKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRßGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRß with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRß), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRß knockout models alongside their DNA binding-deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRß play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects.

Mechanical control of neural plate folding by apical domain alteration.

Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding is not well understood. At the onset of Xenopus neural tube folding, we observed alternation of apically constricted and apically expanded cells. This apical domain heterogeneity was accompanied by biased cell orientation along the anteroposterior axis, especially at neural plate hinges, and required planar cell polarity signaling. Vertex models suggested that dispersed isotropically constricting cells can cause the elongation of adjacent cells. Consistently, in ectoderm, cell-autonomous apical constriction was accompanied by neighbor expansion. Thus, a subset of isotropically constricting cells may initiate neural plate bending, whereas a 'tug-of-war' contest between the force-generating and responding cells reduces its shrinking along the body axis. This mechanism is an alternative to anisotropic shrinking of cell junctions that are perpendicular to the body axis. We propose that apical domain changes reflect planar polarity-dependent mechanical forces operating during neural folding.