Magdalene Michael

King's College London | KCL · Randall Division of Cell and Molecular Biophysics

Integrins are heterodimeric transmembrane receptors that connect the extracellular matrix environment to the actin cytoskeleton via adaptor molecules through assembly of a range of adhesion structures. Recent advances in biochemical, imaging and biophysical methods have enabled a deeper understanding of integrin signalling and their associated regu...

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding factor XIII subunit A, a transglutaminase...

Kindler syndrome (KS) is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localises to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of KS show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective inte...

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By us...

The cortical actomyosin cytoskeleton is found in all non-muscle cells where a key function is to control mechanical force (Salbreux et al., 2012). When coupled to E-cadherin cell-cell adhesion, cortical actomyosin generates junctional tension that influences many aspects of tissue function, organization and morphogenesis (Lecuit and Yap, 2015). Unc...

Non-muscle myosin II (NMII) motor proteins are responsible for generating contractile forces inside eukaryotic cells. There is also a growing interest in the capacity for these motor proteins to influence cell signaling through scaffolding, especially in the context of RhoA GTPase signaling. We previously showed that NMIIA accumulation and stabilit...

In this study we sought to identify how contractility at adherens junctions influences apoptotic cell extrusion. We first found that the generation of effective contractility at steady-state junctions entails a process of architectural reorganization whereby filaments that are initially generated as poorly organized networks of short bundles are th...

To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the act...

Junctional ablation using laser nanoscissors in cells cotransfected with Cont-siRNA and Ecad-GFP revealed that the junctions were under significant tension as indicated by the rapid rate of initial recoil.

Junctional ablation using laser nanoscissors in cells cotransfected with Neo-siRNA and Ecad-GFP revealed the cells were under reduced tension as indicated by the slower rate of initial recoil.

Live-cell imaging of LifeAct-tagged F-actin in cells cotransfected with Cont-siRNA at 2 frame/s (over 200 s) shows that the actin rings under adjacent junctions remain stable.

Supplementary Figures 1-6

Live-cell imaging of cells cotransfected with Cont-siRNA and mGFP at 6 frame/s (over120 s) shows minor fluctuations at the AJ.

Live-cell imaging of cells cotransfected with Neo-siRNA and mGFP at 6 frame/s (over 120s) shows dynamic fluctuations at the AJ, demonstrating a reduction in junctional tension.

Live-cell imaging of LifeAct-tagged F-actin in cells cotransfected with Neo-siRNA at 2 frame/s (over 200 s) shows thinning actin filaments which subsequently disappear (arrow). No clearly defined actin rings are visible.

Cell-cell adhesion physically couples epithelial cells together, contributing to the mechanical coherence that allows epithelia to resist and transmit forces and, ultimately, maintain their physiological integrity. Further, we have come to appreciate that many forces experienced at cell-cell junctions are exerted by neighbouring cells. In other wor...

Advances in cell and developmental biology have often been closely linked to advances in our ability to visualize structure and function at many length and time scales. In this review, we discuss how new imaging technologies and new reagents have provided novel insights into the biology of cadherin-based cell-cell junctions. We focus on three devel...

The behavior of actomyosin critically determines morphologically distinct patterns of contractility found at the interface between adherent cells. One such pattern is found at the apical region (zonula adherens) of cell-cell junctions in epithelia, where clusters of the adhesion molecule E-cadherin concentrate in a static pattern. Meanwhile, E-cadh...

Cadherin junctions arise from the integrated action of cell adhesion, signaling, and the cytoskeleton. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. But how this is coordinated with cadherin adhesion is not known. We now identify cortactin as a key scaffold for actin regula...

E-cadherin cell-cell junctions couple the contractile cortices of epithelial cells together, generating tension within junctions that influences tissue organization. Although junctional tension is commonly studied at the apical zonula adherens, we now report that E-cadherin adhesions induce the contractile actomyosin cortex throughout the apical-la...

Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. Here, we report that Lpd directly binds...

Bullous pemphigoid antigen 1 (BPAG1-e, also known as BP230) is a member of the plakin family of hemidesmosome cytoskeletal linker proteins that is encoded by an isoform of the DST gene. Recently, we reported two unrelated families with homozygous nonsense mutations in this DST isoform that led to ultrastructural loss of hemidesmosomal inner plaques...

Cadherin adhesion receptors are critical components for the maintenance of tissue architecture and organisation during development and in post-embryonic life. These receptors influence the actin cytoskeletal network by controlling its assembly at the junctions. Likewise, the actin cytoskeleton is required for cadherin integrity at cell-cell contact...

The epithelial zonula adherens (ZA) is a specialized adhesive junction where actin dynamics and myosin-driven contractility coincide. The junctional cytoskeleton is enriched in myosin II, which generates contractile force to support junctional tension. It is also enriched in dynamic actin filaments, which are replenished by ongoing actin assembly....

Abbreviations: DST, dystonin; EB, epidermolysis bullosa

Tight regulation of cell motility is essential for many physiological processes, such as formation of a functional nervous system and wound healing. Drosophila Abl negatively regulates the actin cytoskeleton effector protein Ena during neuronal development in flies, and it has been postulated that this may occur through an unknown intermediary. Lam...

MIG-10/RIAM/lamellipodin (MRL) proteins link activated Ras-GTPases with actin regulatory Ena/VASP proteins to induce local changes in cytoskeletal dynamics and cell motility. MRL proteins alter monomeric (G):filamentous (F) actin ratios, but the impact of these changes had not been fully appreciated. We report here that the Drosophila MRL ortholog,...