Pcdh18a regulates endocytosis of E-cadherin during axial mesoderm development in zebrafish

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord

Early developmental specification of the thyroid gland depends on han-expressing surrounding tissue and on FGF signals

The thyroid is an endocrine gland in all vertebrates that develops from the ventral floor of the anterior pharyngeal endoderm. Unravelling the molecular mechanisms of thyroid development helps to understand congenital hypothyroidism caused by the absence or reduction of this gland in newborn humans. Severely reduced or absent thyroid-specific developmental genes concomitant with the complete loss of the functional gland in the zebrafish hands off (han, hand2) mutant reveals the han gene as playing a novel, crucial role in thyroid development. han-expressing tissues surround the thyroid primordium throughout development. Fate mapping reveals that, even before the onset of thyroid-specific developmental gene expression, thyroid precursor cells are in close contact with han-expressing cardiac lateral plate mesoderm. Grafting experiments show that han is required in surrounding tissue, and not in a cell-autonomous manner, for thyroid development. Loss of han expression in the branchial arches and arch-associated cells after morpholino knock-down of upstream regulator genes does not impair thyroid development, indicating that other han-expressing structures, most probably cardiac mesoderm, are responsible for the thyroid defects in han mutants. The zebrafish ace (fgf8) mutant has similar thyroid defects as han mutants, and chemical suppression of fibroblast growth factor (FGF) signalling confirms that this pathway is required for thyroid development. FGF-soaked beads can restore thyroid development in han mutants, showing that FGFs act downstream of or in parallel to han. These data suggest that loss of FGF-expressing tissue in han mutants is responsible for the thyroid defects

Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: All relevant data are within the manuscript and its Supporting Information files.During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems.Biotechnology & Biological Sciences Research Council (BBSRC)Wellcome TrustChinese Scholarship Council (CSC)Medical Research Council (MRC

Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling

Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment

Pcdh18a regulates endocytosis of E-cadherin during axial mesoderm development in zebrafish

This is the final version. Available on open access from Springer via the DOI in this recordThe notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord

Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project)

Objective: To determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia. Design: Evaluator blinded, randomised controlled trial. Setting: 16 clinical sites across 11 European countries, January 2016 to 31 October 2019. Participants: 1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls). Interventions: The multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months. Main outcome measures: The primary outcome was mobility disability (inability to independently walk 400 m in <15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes. Results: Mean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P<0.001) and 36 months (0.26 to 0.73 kg; P<0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34). Conclusions: A multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people

Expedition 391 Preliminary Report : Walvis Ridge Hotspot: drilling Walvis Ridge, Southeast Atlantic Ocean, to test models of ridge hotspot interaction, isotopic zonation, and the hotspot reference frame

Hotspot tracks (quasilinear chains of seamounts, ridges, and other volcanic structures) provide important records of plate motions, as well as mantle geodynamics, magma flux, and mantle source compositions. The Tristan-Gough-Walvis Ridge (TGW) hotspot track, extending from the active volcanic islands of Tristan da Cunha and Gough through a province of guyots and then along Walvis Ridge to the Etendeka flood basalt province, forms one of the most prominent and complex global hotspot tracks. The TGW hotspot track displays a tight linear age progression in which ages increase from the islands to the flood basalts (covering ~135 My). Unlike Pacific tracks, which are simple chains of seamounts that are often compared to chains of pearls, the TGW track is alternately a steep-sided narrow ridge, an oceanic plateau, subparallel linear ridges and chains of seamounts, and areas of what appear to be randomly dispersed seamounts. The track displays isotopic zonation over the last ~70 My. The zonation appears near the middle of the track just before it splits into two to three chains of ridge- and guyot-type seamounts. The older ridge is also overprinted with age-progressive late-stage volcanism, which was emplaced ~30–40 My after the initial eruptions and has a distinct isotopic composition. The plan for Expedition 391 was to drill at six sites, three along Walvis Ridge and three in the seamount (guyot) province, to gather igneous rocks to better understand the formation of track edifices, the temporal and geochemical evolution of the hotspot, and the variation in paleolatitudes at which the volcanic edifices formed. After a delay of 18 days to address a shipboard outbreak of the coronavirus disease 2019 (COVID-19) virus, Expedition 391 proceeded to drill at four of the proposed sites: three sites on the eastern Walvis Ridge around Valdivia Bank, an ocean plateau within the ridge, and one site on the lower flank of a guyot in the Center track, a ridge located between the Tristan subtrack (which extends from the end of Walvis Ridge to the island of Tristan da Cunha) and the Gough subtrack (which extends from Walvis Ridge to the island of Gough). One hole was drilled at Site U1575, located on a low portion of the northeastern Walvis Ridge north of Valdivia Bank. At this location, 209.9 m of sediments and 122.4 m of igneous basement were cored. The latter comprised 10 submarine lava units consisting of pillow, lobate, sheet, and massive lava flows, the thickest of which was ~21 m. Most lavas are tholeiitic, but some alkalic basalts were recovered. A portion of the igneous succession consists of low-Ti basalts, which are unusual because they appear in the Etendeka flood basalts but have not been previously found on Walvis Ridge. Two holes were drilled at Site U1576 on the west flank of Valdivia Bank. The first hole was terminated because a bit jammed shortly after penetrating igneous basement. Hole U1576A recovered a remarkable ~380 m thick sedimentary section consisting mostly of chalk covering a nearly complete sequence from Paleocene to Late Cretaceous (Campanian). These sediments display short and long cyclic color changes that imply astronomically forced and longer term paleoenvironmental changes. The igneous basement yielded 11 submarine lava units ranging from pillows to massive flows, which have compositions varying from tholeiitic basalt to basaltic andesite, the first occurrence of this composition recovered from the TGW track. These units are separated by seven sedimentary chalk units that range in thickness from 0.1 to 11.6 m, implying a long-term interplay of sedimentation and lava eruptions. Coring at Site U1577, on the extreme eastern flank of Valdivia Bank, penetrated a 154 m thick sedimentary section, the bottom ~108 m of which is Maastrichtian–Campanian (possibly Santonian) chalk with vitric tephra layers. Igneous basement coring progressed only 39.1 m below the sediment-basalt contact, recovering three massive submarine tholeiite basalt lava flows that are 4.1, 15.5, and >19.1 m thick, respectively. Paleomagnetic data from Sites U1577 and U1576 indicate that their volcanic basements formed just before the end of the Cretaceous Normal Superchron and during Chron 33r, shortly afterward, respectively. Biostratigraphic and paleomagnetic data suggest an east–west age progression across Valdivia Bank, becoming younger westward. Site U1578, located on a Center track guyot, provided a long and varied igneous section. After coring through 184.3 m of pelagic carbonate sediments mainly consisting of Eocene and Paleocene chalk, Hole U1578A cored 302.1 m of igneous basement. Basement lavas are largely pillows but are interspersed with sheet and massive flows. Lava compositions are mostly alkalic basalts with some hawaiite. Several intervals contain abundant olivine, and some of the pillow stacks consist of basalt with remarkably high Ti content. The igneous sequence is interrupted by 10 sedimentary interbeds consisting of chalk and volcaniclastics and ranging in thickness from 0.46 to 10.19 m. Paleomagnetic data display a change in basement magnetic polarity ~100 m above the base of the hole. Combining magnetic stratigraphy with biostratigraphic data, the igneous section is inferred to span >1 My. Abundant glass from pillow lava margins was recovered at Sites U1575, U1576, and U1578. Although the igneous penetration was only two-thirds of the planned amount, drilling during Expedition 391 obtained samples that clearly will lead to a deeper understanding of the evolution of the Tristan-Gough hotspot and its track. Relatively fresh basalts with good recovery will provide ample samples for geochemical, geochronologic, and paleomagnetic studies. Good recovery of Late Cretaceous and early Cenozoic chalk successions provides samples for paleoenvironmental study

Dynamic Coupling of Pattern Formation and Morphogenesis in the Developing Vertebrate Retina

In this Research Article, Picker et al. show how cells in the retina get their spatial coordinates

A Variant of Fibroblast Growth Factor Receptor 2 (Fgfr2) Regulates Left-Right Asymmetry in Zebrafish

Many organs in vertebrates are left-right asymmetrical located. For example, liver is at the right side and stomach is at the left side in human. Fibroblast growth factor (Fgf) signaling is important for left-right asymmetry. To investigate the roles of Fgfr2 signaling in zebrafish left-right asymmetry, we used splicing blocking morpholinos to specifically block the splicing of fgfr2b and fgfr2c variants, respectively. We found that the relative position of the liver and the pancreas were disrupted in fgfr2c morphants. Furthermore, the left-right asymmetry of the heart became random. Expression pattern of the laterality controlling genes, spaw and pitx2c, also became random in the morphants. Furthermore, lefty1 was not expressed in the posterior notochord, indicating that the molecular midline barrier had been disrupted. It was also not expressed in the brain diencephalon. Kupffer's vesicle (KV) size became smaller in fgfr2c morphants. Furthermore, KV cilia were shorter in fgfr2c morphants. We conclude that the fgfr2c isoform plays an important role in the left-right asymmetry during zebrafish development

A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation

Somitogenesis, the formation of the body's primary segmental structure common to all vertebrate development, requires coordination between biological mechanisms at several scales. Explaining how these mechanisms interact across scales and how events are coordinated in space and time is necessary for a complete understanding of somitogenesis and its evolutionary flexibility. So far, mechanisms of somitogenesis have been studied independently. To test the consistency, integrability and combined explanatory power of current prevailing hypotheses, we built an integrated clock-and-wavefront model including submodels of the intracellular segmentation clock, intercellular segmentation-clock coupling via Delta/Notch signaling, an FGF8 determination front, delayed differentiation, clock-wavefront readout, and differential-cell-cell-adhesion-driven cell sorting. We identify inconsistencies between existing submodels and gaps in the current understanding of somitogenesis mechanisms, and propose novel submodels and extensions of existing submodels where necessary. For reasonable initial conditions, 2D simulations of our model robustly generate spatially and temporally regular somites, realistic dynamic morphologies and spontaneous emergence of anterior-traveling stripes of Lfng. We show that these traveling stripes are pseudo-waves rather than true propagating waves. Our model is flexible enough to generate interspecies-like variation in somite size in response to changes in the PSM growth rate and segmentation-clock period, and in the number and width of Lfng stripes in response to changes in the PSM growth rate, segmentation-clock period and PSM length