Biomedical subjects

Scott Fraser

Publications and source records attributed to Scott Fraser.

3 recordsLinked to original sources

PubMed2003

Distinct modes of floor plate induction in the chick embryo.

To begin to reconcile models of floor plate formation in the vertebrate neural tube, we have performed experiments aimed at understanding the development of the early floor plate in the chick embryo. Using real-time analyses of cell behaviour, we provide evidence that the principal contributor to the early neural midline, the future anterior floor plate, exists as a separate population of floor plate precursor cells in the epiblast of the gastrula stage embryo, and does not share a lineage with axial mesoderm. Analysis of the tissue interactions associated with differentiation of these cells to a floor plate fate reveals a role for the nascent prechordal mesoderm, indicating that more than one inductive event is associated with floor plate formation along the length of the neuraxis. We show that Nr1, a chick nodal homologue, is expressed in the nascent prechordal mesoderm and we provide evidence that Nodal signalling can cooperate with Shh to induce the epiblast precursors to a floor-plate fate. These results indicate that a shared lineage with axial mesoderm cells is not a pre-requisite for floor plate differentiation and suggest parallels between the development of the floor plate in amniote and anamniote embryos.

Animals↗

PubMed2002

Modeling a hox gene network in silico using a stochastic simulation algorithm.

The amount of molecular information that has been gathered about Hox cis-regulatory mechanisms allows us to take the next important step: integrating the results and constructing a higher-level model for the interaction and regulation of the Hox genes. Here, we present the results of our investigation into a cis-regulatory network for the early Hox genes. Instead of using conventional differential equation approaches for analyzing the system, we have adopted the use of a stochastic simulation algorithm (SSA) to model the network. The model allows us to track in detail the behavior of each component of a biochemical pathway and to produce computerized movies of the time evolution of the system that is a result of the dynamic interplay of these various components. The simulation is able to reproduce key features of the wild-type pattern of gene expression, and in silico experiments yield results similar to their corresponding in vivo experiments. This analysis shows the utility of using stochastic methods to model biochemical networks. In addition, the model has suggested several intriguing new results that are currently being investigated in vivo.

Algorithms↗

PubMed2002

Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.

PURPOSE: Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes. METHODS: Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region. RESULTS: Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed. CONCLUSIONS: These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.

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