Microtubules tune mechanosensitive cell responses.

Mechanotransduction is a process by which cells sense the mechanical properties of their surrounding environment and adapt accordingly to perform cellular functions such as adhesion, migration and differentiation. Integrin-mediated focal adhesions are major sites of mechanotransduction and their connection with the actomyosin network is crucial for mechanosensing as well as for the generation and transmission of forces onto the substrate. Despite having emerged as major regulators of cell adhesion and migration, the contribution of microtubules to mechanotransduction still remains elusive. Here, we show that talin- and actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation (a tubulin post-translational modification) by promoting the recruitment of α-tubulin acetyltransferase 1 (αTAT1) to focal adhesions. Microtubule acetylation tunes the mechanosensitivity of focal adhesions and Yes-associated protein (YAP) translocation. Microtubule acetylation, in turn, promotes the release of the guanine nucleotide exchange factor GEF-H1 from microtubules to activate RhoA, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction that contributes to mechanosensitive cell adhesion and migration.

The distinct localization of CDC42 isoforms is responsible for their specific functions during migration.

The small G-protein CDC42 is an evolutionary conserved polarity protein and a key regulator of polarized cell functions, including directed cell migration. In vertebrates, alternative splicing gives rise to two CDC42 proteins: the ubiquitously expressed isoform (CDC42u) and the brain isoform (CDC42b), which only differ in their carboxy-terminal sequence, including the CAAX motif essential for their association with membranes. We show that these divergent sequences do not directly affect the range of CDC42's potential binding partners but indirectly influence CDC42-driven signaling by controlling the subcellular localization of the two isoforms. In astrocytes and neural precursors, which naturally express both variants, CDC42u associates with the leading-edge plasma membrane of migrating cells, where it recruits the Par6-PKCζ complex to fulfill its polarity function. In contrast, CDC42b mainly localizes to intracellular membrane compartments, where it regulates N-WASP-mediated endocytosis. Both CDC42 isoforms contribute their specific functions to promote the chemotaxis of neural precursors, demonstrating that their expression pattern is decisive for tissue-specific cell behavior.

The RECAPACITA project: Description of the clinical, neuropsychological and functional profile of a sample of people with severe mental disorder and legal capacity modification in Spain.

Severe mental disorder (SMD) includes people with long-term mental disorders, disability and social dysfunction. The mental capacity evaluation of the people has been a key aspect in legislative systems around the world and different proposals have been made. In countries like Spain, until 2021, the mental capacity of individuals was assessed by means of legal proceedings. In the last years, there has been a notable increase in the number of claims for legal incapacity, but no data are available on the total number of persons with CM, neither on the specific pathologies, or clinical and cognitive profiles. In view of the total absence of data on the profile of people with SMD and modification of capacity, the RECAPACITA study was born. This study includes patients with SMD and CM, as well as those without CM, with the aim to describe exhaustively their clinical, neuropsychological and functional profile of people with SMD and CM, as well as obtaining a basic description of the social environment. OBJECTIVES: To describe CM in SMD, to identify clinical diagnoses, clinical severity and neuropsychological deterioration. METHODS: Cross-sectional descriptive study. 77 adult patients with SMD and CM, inpatients from the mental health sector of the Parc Sanitari Sant Joan de Déu (Spain), outpatients linked to the community rehabilitation services (CRS), and penitentiary inmates. CM, sociodemographic, clinical, functional and neuropsychological data are collected. RESULTS: In the sample, 59.5% present total CM. 74.7% are men (mean: 52.5 years). 87,0% have a diagnosis of schizophrenia. The estimated premorbid IQ is 91.4. The Global Assessment of Functioning (GAF) had a mean of 50.5, the "Clinical Global Impression Scale" (CGI) was 4.6 and Scale Unawareness of Mental Disorders (SUMD) was 9.28. The cognitive results shows a profile with slow proceeding speed (mean scale score: 6.6), good working memory (mean SC: 8.3) and adequate verbal comprehension (mean SC: 7.3). In memory, coding is altered (Pz: -1.9), and long-term spontaneous recall (Pz: -2.3). In abstract reasoning, a slight alteration is obtained (Mean SC: 6), as well as in semantic fluency (Mean SC: 6.3), phonological (Mean SC: 5.9), and inhibitory capacity (Mean SC: 5.7). CONCLUSIONS: Most of the sample are men with schizophrenia, with a total MC assumed by a tutelary foundation. They show a moderate alteration in global functioning and clinical global impression, with partial awareness of the disease. They present dysexecutive mild cognitive impairment, with poor memory coding and free retrieval capacity, and a normal IQ, adequate verbal comprehension and working memory. This study is the first to present objective data on the psychiatric, functional and cognitive status of a group of patients with CM. Such research could be a good starting point to address a topic of great interest from the health, social and legal point of view of the CM processes of people with SMD.

Absence of detection of highly pathogenic H5N1 in migratory waterfowl in southern France in 2005-2006.

During fall 2005, the rapid and wide spread of highly pathogenic (HP) H5N1 avian influenza viruses (AIV) outside Asia alerted European health authorities. Because of abnormal and recurrent field mortality, wild migratory birds were considered to be the main dispersing agent of the virus at an intercontinental scale. European wintering wetlands, such as the Camargue (Rhône delta, France), are identified as potential hot spots for the risk of introduction and transmission of bird-borne diseases. In this study, we investigated the role of migratory waterbirds (mainly ducks) in the spread of HP H5N1 viruses. We combined molecular analysis of living and freshly killed birds with population surveillance (aerial censuses and death surveillance). We sampled 1345 birds belonging to 17 waterbird species (3 orders) in the Camargue between September 2005 and March 2006. The prevalence of AIV was 1.8%. We did not detect HP H5N1 virus. Population censuses did not reveal any population decreases nor abnormal mortalities. We discuss, in the light of these results, the implication of wild migratory ducks in the arrival of HP H5N1 AIV in Europe.

Neuralized regulates Crumbs endocytosis and epithelium morphogenesis via specific Stardust isoforms.

Crumbs (Crb) is a conserved determinant of apical membrane identity that regulates epithelial morphogenesis in many developmental contexts. In this study, we identify the Crb complex protein Stardust (Sdt) as a target of the E3 ubiquitin ligase Neuralized (Neur) in Drosophila melanogaster Neur interacts with and down-regulates specific Sdt isoforms containing a Neur binding motif (NBM). Using a CRISPR (clustered regularly interspaced short palindromic repeats)-induced deletion of the NBM-encoding exon, we found that Sdt is a key Neur target and that Neur acts via Sdt to down-regulate Crb. We further show that Neur promotes the endocytosis of Crb via the NBM-containing isoforms of Sdt. Although the regulation of Crb by Neur is not strictly essential, it contributes to epithelium remodeling in the posterior midgut and thereby facilitates the trans-epithelial migration of the primordial germ cells in early embryos. Thus, our study uncovers a novel regulatory mechanism for the developmental control of Crb-mediated morphogenesis.

Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila.

Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial-apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal-ventral axis.