Biomedical subjects

Thomas Edlund

Publications and source records attributed to Thomas Edlund.

7 recordsLinked to original sources

PubMed2006

In vitro and in vivo differentiation of boundary cap neural crest stem cells into mature Schwann cells.

Boundary cap cells can generate neurons as well as peripheral glia during embryonic development (Maro, G.S., Vermeren, M., Voiculescu, O., Melton, L., Cohen, J., Charnay, P., Topilko, P., 2004. Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS. Nat Neurosci. 7 (9), 930-938), and, recently, the boundary cap was shown to contain multipotent stem cells (Hjerling-Leffler, J., Marmigère, F., Heglind, M., Cederberg, A., Koltzenburg, M., Enerbäck, S., Ernfors, P., 2005. The boundary cap, a source of neural crest stem cells generating multiple sensory neuron subtypes. Development. 132 (11), 2623-2632). The ability of stem cells to generate mature functional glial phenotypes has not been addressed. In this study, we have explored the competence of boundary neural crest stem cells (bNCSCs) to differentiate into mature functional Schwann cells (SCs) in vitro and in vivo. bNCSCs failed to differentiate into SCs in vitro when cultured in a defined media and in vivo when grafted into adult rat sciatic nerves. However, in the presence of neuregulins, during long-term cultures, the majority of bNCSCs differentiated into SCs. After analysis of the in vivo expression of Sox2, Sox10, S100, GFAP, fibronectin and Krox20 in the glial lineages, we used these markers to characterize differentiation of the bNCSCs. Gliogenesis of bNCSCs proceeded similar to that in vivo by sequentially adopting a SC precursor and immature Schwann cell before maturing into myelinating and non-myelinating SCs. In co-culture with explanted dorsal root ganglia (DRG) as well as in vivo in transplants to the axotomized sciatic nerve, these bNCSC-derived SCs myelinated axons as shown by ensheathing of neuronal processes and expression of myelin basic proteins (MBP). These results show that, under appropriate conditions, bNCSCs can generate mature SCs that are functional and can myelinate axons in regenerating nerves.

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PubMed2006

Convergent Wnt and FGF signaling at the gastrula stage induce the formation of the isthmic organizer.

The development of the vertebrate brain depends on the formation of local organizing centres within the neural tube that express secreted signals that refine local neural progenitor identity. The isthmic organizer (IsO) forms at the isthmic constriction and is required for the growth and ordered development of mesencephalic and metencephalic structures. The formation of the IsO, which is characterized by the generation of a complex pattern of cells at the midbrain-hindbrain boundary, has been described in detail. However, when neural plate cells are initially instructed to form the IsO, the molecular nature of the inductive signals remain poorly defined. We now provide evidence that convergent Wnt and FGF signaling at the gastrula stage are required to generate the complex polarized pattern of cells characteristic of the IsO, and that Wnt and FGF signals in combination are sufficient to reconstruct, in naïve forebrain cells, an IsO-like structure that exhibits an organizing activity that mimics the endogenous IsO when transplanted into the diencephalon of chick embryos.

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PubMed2006

An early role for WNT signaling in specifying neural patterns of Cdx and Hox gene expression and motor neuron subtype identity.

The link between extrinsic signaling, progenitor cell specification and neuronal subtype identity is central to the developmental organization of the vertebrate central nervous system. In the hindbrain and spinal cord, distinctions in the rostrocaudal identity of progenitor cells are associated with the generation of different motor neuron subtypes. Two fundamental classes of motor neurons, those with dorsal (dMN) and ventral (vMN) exit points, are generated over largely non-overlapping rostrocaudal domains of the caudal neural tube. Cdx and Hox genes are important determinants of the rostrocaudal identity of neural progenitor cells, but the link between early patterning signals, neural Cdx and Hox gene expression, and the generation of dMN and vMN subtypes, is unclear. Using an in vitro assay of neural differentiation, we provide evidence that an early Wnt-based program is required to interact with a later retinoic acid- and fibroblast growth factor-mediated mechanism to generate a pattern of Cdx and Hox profiles characteristic of hindbrain and spinal cord progenitor cells that prefigure the generation of vMNs and dMNs.

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PubMed2004

Retinoic acid signalling specifies intermediate character in the developing telencephalon.

The organisation of the telencephalon into its major structures depends on its early regionalisation along the dorsoventral axis. Previous studies have provided evidence that sonic hedgehog (SHH) is required for the generation of telencephalic cells of ventral character, and that sequential WNT and fibroblast growth factor (FGF) signalling specifies cells of dorsal telencephalic character. However, the signalling mechanisms that specify telencephalic cells of an intermediate character remain to be defined. We provide evidence here that retinoic acid has a crucial role in specifying telencephalic progenitor cells of intermediate character.

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PubMed2003

Specification of dorsal telencephalic character by sequential Wnt and FGF signaling.

Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.

Aging↗

PubMed2002

Progressive induction of caudal neural character by graded Wnt signaling.

Early in differentiation, all neural cells have a rostral character. Only later do posteriorly positioned neural cells acquire characteristics of caudal forebrain, midbrain and hindbrain cells. Caudalization of neural tissue in the chick embryo apparently involves the convergent actions of (i) fibroblast growth factor (FGF) signaling and (ii) signaling from the caudal paraxial mesoderm, or 'PMC activity', which has not yet been defined molecularly. Here we report evidence that Wnt signaling underlies PMC activity, and show that Wnt signals act directly and in a graded manner on anterior neural cells to induce their progressive differentiation into caudal forebrain, midbrain and hindbrain cells.

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PubMed2002

Nitric oxide and blood pressure in mice lacking extracellular-superoxide dismutase.

Nitric oxide is a major vasorelaxant and regulator of the blood pressure. The blood vessels contain several active sources of the superoxide radical, which reacts avidly with nitric oxide to form noxious peroxynitrite. There are large amounts of extracellular-superoxide dismutase (EC-SOD) in the vascular wall. To evaluate the importance of EC-SOD for the physiology of nitric oxide, here we studied the blood pressure in mice lacking the enzyme. In chronically instrumented non-anaesthetized mice there was no difference in mean arterial blood pressure between wild-type controls and EC-SOD mutants. Extensive inhibition of nitric oxide synthases with N-monomethyl-L-arginine however resulted in a larger increase in blood pressure, and infusion of the nitric oxide donor nitrosoglutathione caused less reduction in blood pressure in the EC-SOD null mice. We interpret the alterations to be caused by a moderately increased consumption of nitric oxide by the superoxide radical in the EC-SOD null mice. One role of EC-SOD may be to preserve nitric oxide, a function that should be particularly important in vascular pathologies, in which large increases in superoxide formation have been documented.

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