Biomedical subjects

David Edgar

Publications and source records attributed to David Edgar.

7 recordsLinked to original sources

PubMed2005

A simplified laminin nomenclature.

A simplification of the laminin nomenclature is presented. Laminins are multidomain heterotrimers composed of alpha, beta and gamma chains. Previously, laminin trimers were numbered with Arabic numerals in the order discovered, that is laminins-1 to -5. We introduce a new identification system for a trimer using three Arabic numerals, based on the alpha, beta and gamma chain numbers. For example, the laminin with the chain composition alpha5beta1gamma1 is termed laminin-511, and not laminin-10. The current practice is also to mix two overlapping domain and module nomenclatures. Instead of the older Roman numeral nomenclature and mixed nomenclature, all modules are now called domains. Some domains are renamed or renumbered. Laminin epidermal growth factor-like (LE) domains are renumbered starting at the N-termini, to be consistent with general protein nomenclature. Domain IVb of alpha chains is named laminin 4a (L4a), domain IVa of alpha chains is named L4b, domain IV of gamma chains is named L4, and domain IV of beta chains is named laminin four (LF). The two coiled-coil domains I and II are now considered one laminin coiled-coil domain (LCC). The interruption in the coiled-coil of beta chains is named laminin beta-knob (Lbeta) domain. The chain origin of a domain is specified by the chain nomenclature, such as alpha1L4a. The abbreviation LM is suggested for laminin. Otherwise, the nomenclature remains unaltered.

Animals↗

PubMed2004

Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates.

This study investigates the establishment of alternative cell fates during embryoid body differentiation when ES cells diverge into two epithelia simulating the pre-gastrulation endoderm and ectoderm. We report that endoderm differentiation and endoderm-specific gene expression, such as expression of laminin 1 subunits, is controlled by GATA6 induced by FGF. Subsequently, differentiation of the non-polar primitive ectoderm into columnar epithelium of the epiblast is induced by laminin 1. Using GATA6 transformed Lamc1-null endoderm-like cells, we demonstrate that laminin 1 exhibited by the basement membrane induces epiblast differentiation and cavitation by cell-to-matrix/matrix-to-cell interactions that are similar to the in vivo crosstalk in the early embryo. Pharmacological and dominant-negative inhibitors reveal that the cell shape change of epiblast differentiation requires ROCK, the Rho kinase. We also show that pluripotent ES cells display laminin receptors; hence, these stem cells may serve as target for columnar ectoderm differentiation. Laminin is not bound by endoderm derivatives; therefore, the sub-endodermal basement membrane is anchored selectively to the ectoderm, conveying polarity to its assembly and to the differentiation induced by it. Unique to these interactions is their flow through two cell layers connected by laminin 1 and their involvement in the differentiation of two epithelia from the same stem cell pool: one into endoderm controlled by FGF and GATA6; and the other into epiblast regulated by laminin 1 and Rho kinase.

Basement Membrane↗

PubMed2004

The topographical regulation of embryonic stem cell differentiation.

The potential use of pluripotent stem cells for tissue repair or replacement is now well recognized. While the ability of embryonic stem (ES) cells to differentiate into all cells of the body is undisputed, their use is currently restricted by our limited knowledge of the mechanisms controlling their differentiation. This review discusses recent work by ourselves and others investigating the intercellular signalling events that occur within aggregates of mouse ES cells. The work illustrates that the processes of ES cell differentiation, epithelialization and programmed cell death are dependent upon their location within the aggregates and coordinated by the extracellular matrix. Establishment of the mechanisms involved in these events is not only of use for the manipulation of ES cells themselves, but it also throws light on the ways in which differentiation is coordinated during embryogenesis.

Animals↗

PubMed2004

Topography, stem cell behaviour, and organogenesis.

The fundamental problem of development is to explain how the progeny of a single cell, the fertilised egg, differentiates to form all the tissues of the body in the right place at the right time. It has only been during the last couple of years that the mechanisms and molecules mediating interactions between cells and tissues have begun to be delineated. This article reviews some of these recent studies. Sequences of topographically defined cellular interactions lead not only to the development of the body but also to the obvious and remarkable inference that the body more or less automatically builds itself.

Cell Differentiation↗

PubMed2003

The role of laminin in embryonic cell polarization and tissue organization.

Genetic analyses have revealed that members of the laminin glycoprotein family are required for basement membrane assembly and cell polarization, with subsequent effects on cell survival and tissue organization during metazoan embryogenesis. These functions depend upon the cooperation between laminin polymerization and cell anchorage mediated via interactions with beta1-integrins, dystroglycan, and other cell surface receptors.

Animals↗

PubMed2002

Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation.

Laminin-1 is essential for early embryonic basement membrane assembly and differentiation. Several steps can be distinguished, i.e., the expression of laminin and companion matrix components, their accumulation on the cell surface and assembly into basement membrane between endoderm and inner cell mass, and the ensuing differentiation of epiblast. In this study, we used differentiating embryoid bodies derived from mouse embryonic stem cells null for gamma1-laminin, beta1-integrin and alpha/beta-dystroglycan to dissect the contributions of laminin domains and interacting receptors to this process. We found that (a) laminin enables beta1-integrin-null embryoid bodies to assemble basement membrane and achieve epiblast with beta1-integrin enabling expression of the laminin alpha1 subunit; (b) basement membrane assembly and differentiation require laminin polymerization in conjunction with cell anchorage, the latter critically dependent upon a heparin-binding locus within LG module-4; (c) dystroglycan is not uniquely required for basement membrane assembly or initial differentiation; (d) dystroglycan and integrin cooperate to sustain survival of the epiblast and regulate laminin expression; and (e) laminin, acting via beta1-integrin through LG1-3 and requiring polymerization, can regulate dystroglycan expression.

Animals↗

PubMed2002

A low serum sICAM-1 level may assist in the exclusion of neonatal infection.

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) in 46 samples from 46 infants undergoing intensive care were studied. Residual serum remaining after routine electrolyte analysis was utilised. sICAM-1 levels were determined by ELISA. Blind retrospective chart review was employed to determine whether infants were infected. Serum levels were significantly elevated in infants with proven and probable infection, compared with non-infected infants (p < 0.001). sICAM-1 levels in serum were comparable to levels previously established in plasma samples. The results suggest that serum sICAM-1 measurement is a simple and robust test that differentiates infected from non-infected infants and that a low level of serum sICAM-1 may particularly assist in the exclusion of infection.

Bacterial Infections↗