Keeping Sonic Hedgehog Under the Thumb: Genetic Regulation of Limb Development

The development of a single fertilised egg into a complete organism with all its different cell-types is a complicated process. Each cell needs to know its relative position to the rest of the body, in order to know whether it should become bone, muscle, blood vessel, skin or any of the other cell types present. Traditionally the limb has been used as a model to study the mechanisms involved in patterning. For one, it is accessible for manipulations in the chicken egg, a feature that has been extensively used in classical embryology. Moreover, the limb is not essential for embryonic survival, allowing experiments that destroy the limb organisation to be followed over time. As a result, the development of the limb has been well characterised. Genetic analyses in the mouse have also added to our insights in limb development. The basic mechanisms during the development of the upper limb in chick and mouse (and human) are similar. The following chapter will describe the results from experiments performed either in mouse or chick and can be extrapolated to the human situation. Where differences are known to exist, they are indicated specifically. In this thesis, I will discuss the limb bud as if it were a pre-existing entity without connection to the rest of the body. This of course is a simplification of reality. Many of the signalling molecules and mechanisms discussed below are essential for patterning other parts of the body besides the limb buds. For example, Sonic Hedgehog is expressed in the developing notochord where it triggers a signalling cascade involving Wnt signalling, BMPs and FGFs, patterning the neural tube above

Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that i

Gene expression profiling in uveal melanoma: Two regions on 3p related to prognosis

PURPOSE. Although studies on uveal melanoma (UM) revealed prognostic significance of chromosomal aberrations, they resulted in classification errors in survival prediction.