Biology subjects

Yelin, R.

Publications and source records attributed to Yelin, R..

5 recordsLinked to original sources

bioRxiv2024

Stored Elastic Bending Tension as a Mediator of Embryonic Body Folding

During development, amniote vertebrate embryos transform from a flat, multi-layered sheet into a three-dimensional cylindrical form, through ventral folding of the lateral sides of the sheet (the lateral plate, LP) and their fusion in the ventral midline. Although this basic aspect of vertebrate body plan formation has long been described, it is not understood at the mechanistic level. Each side of the LP is comprised of two tissue layers: a dorsal somatopleure (Sop) of pseudostratified coelomic epithelium, extracellular matrix (ECM) and ectoderm, and a ventral splanchnopleure (Spl) of similar construction except with endoderm instead of ectoderm. Using a chick embryo slice system we find that the flat stage is actually a poised balance of opposing elastic bending tensions, with dorsal bending tension in the Sop opposing ventral bending tension in the Spl. An intact extracellular matrix is required for generating the bending tensions, as localized enzymatic digestion of Sop or Spl ECM dissipates tension, while removal of the endodermal or ectodermal layers has no effect. As development proceeds, the Sop undergoes Epithelial-Mesenchymal Transition, ECM fragmentation and dissipation of dorsal bending tension, while the Spl ECM and ventral bending tension remain intact, thus changing the balance of bending forces in the LP to promote ventral folding. Consistent with these findings, interference with the elastic ECM component fibrillin in the Spl in vivo reduces stored bending tension and perturbs ventral body folding. A generalizable conceptual model is presented in which embryonic growth, in the context of specific embryonic geometrical constraints, leads to accumulation of bending tension in the LP ECM, which is harnessed to drive body folding.

developmental biology↗

bioRxiv2023

An atypical basement membrane forms a midline barrier in left-right asymmetric gut development

Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1+ midline barrier to separate the two sides of the embryo, without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals are poorly understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.

developmental biology↗

bioRxiv2022

Regulation of Aortic Morphogenesis and VE-Cadherin Dynamics by VEGF

In amniote vertebrates, the definitive dorsal aorta is formed by the side-to-side fusion of two primordial aortic endothelial tubes. Formation of the definitive dorsal aorta requires extensive cellular migrations and rearrangements of the primordial tubes in order to generate a single fused vessel located at the embryonic ventral midline. This study examines the role of VEGF signaling in the generation of the definitive dorsal aorta. Through gain- and loss-of-function studies in vivo in the chick embryo, we document a requirement for VEGF signaling in growth and migration of the paired primordia, and identify a developmental window in which aorta development is particularly sensitive to VEGF signaling. We also find that VEGF signaling regulates the intracellular distribution between membrane and cytoplasm of the cell-cell adhesion molecule VE-Cadherin in aortic endothelial cells in vivo, suggesting a possible mechanism for how VEGF regulates aortic endothelial cell dynamics during the fusion process.

developmental biology↗

bioRxiv2022

A Morphogenetic Wave that Generates Mesenchymal-to-Epithelial Transition in the Lateral Plate Mesoderm

Most mesodermal cells undergo multiple cycles of transition between an epithelial and mesenchymal state during embryonic development. While many studies have addressed the process of epithelial-to-mesenchymal transition (EMT), comparatively less is known regarding the complementary process, mesenchymal-to-epithelial transition (MET), which is essential for organogenesis and has also been proposed to be important for cancer metastasis. The current study investigated MET using the lateral plate mesoderm (LPM) of the chick embryo as a model system. We find that MET in the LPM proceeds as a wave, which divides the LPM into distinct mesenchymal, transition, and epithelial zones. In the multilayered mesenchymal zone, many apical epithelial markers, including N-Cadherin (N-Cad), Par-3 and Zo-1, but not atypical protein kinase C (aPKC), are detected as dispersed, partially co-localizing aggregates associated with cell-cell contacts. The transition zone is characterized by the appearance of aPKC and the formation of rosette-like structures characterized by wedge-shaped cells that are apical-basal polarized, with strong co-localization of apical polarity markers, but not yet arranged into distinct epithelial sheets. The transition zone is also enriched in mitotic cells. Subsequently, the rosettes resolve into two well-defined epithelial sheets that constitute the coelomic epithelium, the lining of the internal body cavity. Prior to any overt signs of apical-basal polarity, fibronectin (FN) begins to accumulate at the future basal side of the incipient epithelium. Interference with Extracellular Matrix (ECM)-integrin signaling through disruption of focal adhesion kinase (FAK) or Talin function hindered the normal progression of the epithelialization process. Cells with disrupted FAK or Talin function retained mesenchymal-like characteristics with respect to cellular morphology and apical-basal marker distribution. We propose a two-stage process for MET in the LPM. Initially, in the polarization phase, ECM-integrin-dependent signaling imparts apical-basal polarity, culminating in the activation of aPKC, to drive cell intercalation and rosette formation. Subsequently in the resolution phase, polarized rosette cells, perhaps facilitated by the weakening of cell-cell interactions that occurs during mitosis, expand their apical surface, and spread out to form new connections laterally to their fully epithelial neighbors. This sequence of events is propagated as a wave through the LPM, thus generating an integrated coelomic epithelium.

cell biology↗

bioRxiv2020

A Single Dose of Self-Transcribing and Replicating RNA Based SARS-CoV-2 Vaccine Produces Protective Adaptive Immunity In Mice

A self-transcribing and replicating RNA (STARR) based vaccine (LUNAR(R)-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolong SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell mediated immunity produced a strong viral antigen specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for IFN-{gamma} and IL-4 positive CD4+ T helper lymphocytes as well as anti-spike glycoprotein IgG2a/IgG1 ratios supported a strong Th1 dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 g and 10 g doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of Lunar-COV19 as a single dose vaccine.

immunology↗