Biomedical subjects

Nicoletta Kessaris

Publications and source records attributed to Nicoletta Kessaris.

7 recordsLinked to original sources

PubMed2006

SoxD proteins influence multiple stages of oligodendrocyte development and modulate SoxE protein function.

The myelin-forming oligodendrocytes are an excellent model to study transcriptional regulation of specification events, lineage progression, and terminal differentiation in the central nervous system. Here, we show that the group D Sox transcription factors Sox5 and Sox6 jointly and cell-autonomously regulate several stages of oligodendrocyte development in the mouse spinal cord. They repress specification and terminal differentiation and influence migration patterns. As a consequence, oligodendrocyte precursors and terminally differentiating oligodendrocytes appear precociously in spinal cords deficient for both Sox proteins. Sox5 and Sox6 have opposite functions than the group E Sox proteins Sox9 and Sox10, which promote oligodendrocyte specification and terminal differentiation. Both genetic as well as molecular evidence suggests that Sox5 and Sox6 directly interfere with the function of group E Sox proteins. Our studies reveal a complex regulatory network between different groups of Sox proteins that is essential for proper progression of oligodendrocyte development.

Animals↗

PubMed2006

Oligodendrocyte wars.

Oligodendrocyte precursors first arise in a restricted ventral part of the embryonic spinal cord and migrate laterally and dorsally from there. Later, secondary sources develop in the dorsal cord. Normally, the ventrally-derived precursors compete with and suppress their dorsal counterparts. There are also ventral and dorsal sources in the forebrain, but here the more dorsal precursors prevail and the ventral-most lineage is eliminated during postnatal life. How do the different populations compete and what is the outcome of the competition? Do different embryonic origins signify different functional subgroups of oligodendrocyte?

Animals↗

PubMed2005

Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage.

The developmental origin of oligodendrocyte progenitors (OLPs) in the forebrain has been controversial. We now show, by Cre-lox fate mapping in transgenic mice, that the first OLPs originate in the medial ganglionic eminence (MGE) and anterior entopeduncular area (AEP) in the ventral forebrain. From there, they populate the entire embryonic telencephalon including the cerebral cortex before being joined by a second wave of OLPs from the lateral and/or caudal ganglionic eminences (LGE and CGE). Finally, a third wave arises within the postnatal cortex. When any one population is destroyed at source by the targeted expression of diphtheria toxin, the remaining cells take over and the mice survive and behave normally, with a normal complement of oligodendrocytes and myelin. Thus, functionally redundant populations of OLPs compete for space in the developing brain. Notably, the embryonic MGE- and AEP-derived population is eliminated during postnatal life, raising questions about the nature and purpose of the competition.

Animals↗

PubMed2005

Neural crest origins of the neck and shoulder.

The neck and shoulder region of vertebrates has undergone a complex evolutionary history. To identify its underlying mechanisms we map the destinations of embryonic neural crest and mesodermal stem cells using Cre-recombinase-mediated transgenesis. The single-cell resolution of this genetic labelling reveals cryptic cell boundaries traversing the seemingly homogeneous skeleton of the neck and shoulders. Within this assembly of bones and muscles we discern a precise code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey as they form muscle scaffolds. The neural crest anchors the head onto the anterior lining of the shoulder girdle, while a Hox-gene-controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton. The skeleton that we identify as neural crest-derived is specifically affected in human Klippel-Feil syndrome, Sprengel's deformity and Arnold-Chiari I/II malformation, providing insights into their likely aetiology. We identify genes involved in the cellular modularity of the neck and shoulder skeleton and propose a new method for determining skeletal homologies that is based on muscle attachments. This has allowed us to trace the whereabouts of the cleithrum, the major shoulder bone of extinct land vertebrate ancestors, which seems to survive as the scapular spine in living mammals.

Amphibians↗

PubMed2005

A subset of oligodendrocytes generated from radial glia in the dorsal spinal cord.

Many oligodendrocytes in the spinal cord are derived from a region of the ventral ventricular zone (VZ) that also gives rise to motoneurons. Cell fate specification in this region depends on sonic hedgehog (Shh) from the notochord and floor plate. There have been suggestions of an additional source(s) of oligodendrocytes in the dorsal spinal cord. We revisited this idea by Cre-lox fate-mapping in transgenic mice. We found that a subpopulation of oligodendrocytes is generated from the Dbx1-expressing domain of the VZ, spanning the dorsoventral midline. Dbx-derived oligodendrocytes comprise less than 5% of the total; they are formed late during embryogenesis by transformation of radial glia and settle mainly in the lateral white matter. Development of Dbx-derived oligodendrocytes in vitro can occur independently of Shh but requires FGF signalling. Dbx-expressing precursors also generate astrocytes and interneurons, but do not contribute to the ependymal layer of the postnatal spinal cord.

Animals↗

PubMed2004

Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors.

Sonic hedgehog (SHH) and fibroblast growth factor 2 (FGF2) can both induce neocortical precursors to express the transcription factor OLIG2 and generate oligodendrocyte progenitors (OLPs) in culture. The activity of FGF2 is unaffected by cyclopamine, which blocks Hedgehog signalling, demonstrating that the FGF pathway to OLP production is Hedgehog independent. Unexpectedly, SHH-mediated OLP induction is blocked by PD173074, a selective inhibitor of FGF receptor (FGFR) tyrosine kinase. SHH activity also depends on mitogen-activated protein kinase (MAPK) but SHH does not itself activate MAPK. Instead, constitutive activity of FGFR maintains a basal level of phosphorylated MAPK that is absolutely required for the OLIG2- and OLP-inducing activities of SHH. Stimulating the MAPK pathway with a retrovirus encoding constitutively active RAS shows that the requirement for MAPK is cell-autonomous, i.e. MAPK is needed together with SHH signalling in the cells that become OLPs.

Animals↗

PubMed2002

An 'oligarchy' rules neural development.

Recent reports show that Olig genes, which encode the basic helix-loop-helix Olig transcription factors, are essential for development of oligodendrocytes. Surprisingly, Olig function is also required for formation of somatic motor neurons. These findings alter our views of how the oligodendrocyte lineage is generated and raise further questions about the underlying developmental relationships between neurons and glia.

Animals↗