A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System

The Wnt pathway is a key signalling cascade that regulates the formation and function of neuronal circuits. The main receptors for Wnts are Frizzled (Fzd) that mediate diverse functions such as neurogenesis, axon guidance, dendritogenesis, synapse formation, and synaptic plasticity. These processes are crucial for the assembly of functional neuronal circuits required for diverse functions ranging from sensory and motor tasks to cognitive performance. Indeed, aberrant Wnt–Fzd signalling has been associated with synaptic defects during development and in neurodegenerative conditions such as Alzheimer’s disease. New studies suggest that the localisation and stability of Fzd receptors play a crucial role in determining Wnt function. Post-translational modifications (PTMs) of Fzd are emerging as an important mechanism that regulates these Wnt receptors. However, only phosphorylation and glycosylation have been described to modulate Fzd function in the central nervous system (CNS). In this review, we discuss the function of Fzd in neuronal circuit connectivity and how PTMs contribute to their function. We also discuss other PTMs, not yet described in the CNS, and how they might modulate the function of Fzd in neuronal connectivity. PTMs could modulate Fzd function by affecting Fzd localisation and stability at the plasma membrane resulting in local effects of Wnt signalling, a feature particularly important in polarised cells such as neurons. Our review highlights the importance of further studies into the role of PTMs on Fzd receptors in the context of neuronal connectivity

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology

RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer.

In order to metastasise, triple negative breast cancer (TNBC) must make dynamic changes in cell shape. The shape of all eukaryotic cells is regulated by Rho Guanine Nucleotide Exchange Factors (RhoGEFs), which activate Rho-family GTPases in response to mechanical and informational cues. In contrast, Rho GTPase-activating proteins (RhoGAPs) inhibit Rho GTPases. However, which RhoGEFs and RhoGAPS couple TNBC cell shape to changes in their environment is very poorly understood. Moreover, whether the activity of particular RhoGEFs and RhoGAPs become dysregulated as cells evolve the ability to metastasise is not clear. Towards the ultimate goal of identifying RhoGEFs and RhoGAPs that are essential for TNBC metastasis, we performed an RNAi screen to isolate RhoGEFs and RhoGAPs that contribute to the morphogenesis of the highly metastatic TNBC cell line LM2, and its less-metastatic parental cell line MDA-MB-231. For ~6 million cells from each cell line, we measured 127 different features following the depletion of 142 genes. Using a linear classifier scheme we also describe the morphological heterogeneity of each gene-depleted population

Updating temperature and salinity mean values and trends in the Western Mediterranean: the RADMED project

Postprin

Updating temperature and salinity mean values and trends in the Western Mediterranean: the RADMED project

Postprin

Long-Term Changes in the Water Mass Properties in the Balearic Channels Over the Period 1996–2019

The analysis of a 24-year time series of Conductivity-Temperature-Depth (CTD) casts collected in the Balearic Channels (1996–2019) has allowed detecting and quantifying long-term changes in water mass properties in the Western Mediterranean. For the complete period, the intermediate waters have experienced warming and salting at rates of 1.4°C/100yr and 0.3–0.6/100yr for the Western Intermediate Water, and 1°C/100yr and 0.3–0.4/100yr for the Levantine Intermediate Water. The density of these two water masses has not changed. The deep waters, defined as those denser than 29.1 kg/m3, showed positive trends in temperature, salinity, and density (0.8°C/100yr, 0.2/100yr, and 0.02 kg.m–3/100yr, respectively). The high temporal variability of the upper layer makes the detection of long-term changes more difficult. Nevertheless, combining CTD data with temperature data from the oceanographic station at L’Estartit and simulated data from the NCEP/NCAR reanalysis, it can be established that the Atlantic Water increased its temperature at a rate of 2.1–2.8°C/100yr and likely its salinity at a rate of 0.6/100yr. The water column absorbed heat at a rate equivalent to 1–1.2 W/m2. All these trends are much higher than those reported in previous works (more than double in some cases). The warming of the water column produced an increase in the thermosteric component of sea level. However, this increase was compensated by the decrease in the halosteric component. Besides these changes, other alterations related to the Western Mediterranean Transition have been observed over shorter periods. The temperature and salinity of the intermediate waters increased before the winter of 2004/2005 and then the temperature and salinity of the deep waters increased dramatically in 2005. The density of the deep water reached values unprecedented before 2005. Deep and intermediate waters were uplifted by the presence of such dense deep waters. The arrival of warmer and saltier intermediate waters from the Eastern Mediterranean is also observed, mainly after 2010.Postprin

MEGADES: MEGARA Galaxy Discs Evolution Survey. Data Release I: central fields

The main interest of the Science Team for the exploitation of the MEGARA instrument at the 10.4m Gran Telescopio Canarias (GTC hereafter) is devoted to the study of nearby galaxies, with focus on the research of the history of star formation, and chemical and kinematical properties of disc systems. We refer to this project as MEGADES: MEGARA Galaxy Discs Evolution Survey. The initial goal of MEGADES is to provide a detailed study of the inner regions of nearby disc galaxies, both in terms of their spectrophotometric and chemical evolution, and their dynamical characterisation, by disentangling the contribution of in-situ and ex-situ processes to the history of star formation and effective chemical enrichment of these regions. In addition, the dynamical analysis of these inner regions naturally includes the identification and characterization of galactic winds potentially present in these regions. At a later stage, we will extend this study further out in galactocentric distance. The first stage of this project encompasses the analysis of the central regions of a total of 43 nearby galaxies observed with the MEGARA Integral Field Unit for 114 hours, including both Guaranteed Time and Open Time observations. In this paper we provide a set of all the processed data products available to the community and early results from the analysis of these data regarding stellar continuum, ionized and neutral gas features.Comment: Accepted for publication in Astronomy & Astrophysic

MEGARA-GTC stellar spectral library: I

MEGARA (Multi Espectrografo en GTC de Alta Resolucion para Astronomia) is an optical (3650-9750 Å), fibre-fed, medium-high spectral resolution (R = 6000, 12 000 and 20 000) instrument for the Gran Telescopio CANARIAS (GTC) 10.4-m telescope, commissioned in the summer of 2017, and currently in operation. The scientific exploitation of MEGARA requires a stellar spectra library to interpret galaxy data and to estimate the contribution of the stellar populations. In this paper, we introduce the MEGARA-GTC spectral library, detailing the rationale behind the building of this catalogue. We present the spectra of 97 stars (21 individual stars and 56 members of the globular cluster M15, which are both subsamples taken during the commissioning runs, and 20 stars from our ongoing GTC Open-Time programme). The spectra have R = 20 000 in the HR-R and HR-I set-ups, centred at 6563 and 8633 Å, respectively. We describe the procedures to reduce and analyse the data. Then, we determine the best-fitting theoretical models to each spectrum through a χ^(2) minimization technique, to derive the stellar physical parameters, and we discuss the results. We have also measured some absorption lines and indices. Finally, we introduce our project to complete the library and the data base in order to make the spectra available to the community

Mapping the ionized gas of the metal-poor HII galaxy PHL 293B with MEGARA

Here we report the first spatially resolved spectroscopic study for the galaxy PHL293B using the high-resolution GTC/MEGARA IFU. PHL293B is a local, extremely metal-poor, high ionization galaxy. This makes PHL 293B an excellent analogue for galaxies in the early Universe. The MEGARA aperture (~12.5''x 11.3'') covers the entire PHL 293B main body and its far-reaching ionized gas. We created and discussed maps of all relevant emission lines, line ratios and physical-chemical properties of the ionized ISM. The narrow emission gas appears to be ionized mainly by massive stars according to the observed diganostic line ratios, regardless of the position across the MEGARA aperture. We detected low intensity broad emission components and blueshifted absorptions in the Balmer lines (H$\alpha$,H$\beta$) which are located in the brightest zone of the galaxy ISM. A chemically homogeneity, across hundreds of parsecs, is observed in O/H. We take the oxygen abundance 12+log(O/H)=7.64 $\pm$ 0.06 derived from the PHL293B integrated spectrum as the representative metallicity for the galaxy. Our IFU data reveal for the first time that the nebular HeII4686 emission from PHL 293B is spatially extended and coincident with the ionizing stellar cluster, and allow us to compute its absolute HeII ionizing photon flux. Wolf-Rayet bumps are not detected excluding therefore Wolf-Rayet stars as the main HeII excitation source. The origin of the nebular HeII4686 is discussed.Comment: 14 pages, 9 Figures, 3 Tables; Accepted for publication in MNRA