Below is the lay-abstract from a recently completed project as part of the masters year of my PhD here in Edinburgh. It is pretty much the culmination of 10 weeks of solid immunohistochemistry on mouse fetuses (feti?). While Wnt activity is well established as a major component of forebrain development, it’s actual interactions are less understood. This project aimed to elucidate the link between Wnt and Gli3, on of the myriad factors known to interact with Wnt. (Got my grade back today. It is good. I am pleased.)
Canonical Wnt signaling exhibits a dynamic pattern during forebrain development and is disrupted in the extratoes mouse mutant
The brain is one of the most complex organs in the human body, made up of a number of interacting regions. The most easily recognisable of these regions is the folded structure that takes up most of the room in the skull called the forebrain. The most evolutionarily advanced region of the brain, it is responsible for processing the enormous amounts of sensory data acquired by the five senses and mediating the appropriate cognitive and physical responses. Even more impressive than the functional power of the adult forebrain though, is the fact that it develops from no more than a single sheet of cells in the early embryo.
The process of going from this early neural tissue to the complex adult forebrain is regulated by a large number of interacting genetic pathways that are highly conserved across species as divergent as the fruit fly and the mouse, indicating their importance in brain development. This evolutionarily importance is reflected in the severe brain abnormalities observed when the function of some of the key genes is lost. One of these genes, Gli3, plays a vital role in the correct formation of the top part of the forebrain and is associated with human syndromes such as Pallister-Hall syndrome and Greig cephalopolysyndactyly syndrome when mutated.
This research project presents a detailed analysis of the activity of a specific genetic pathway, the Wnt pathway, known to be very active in the development of the top part of the forebrain, and how it is affected by the loss of the gene Gli3 in a mouse model. Our results show that the loss of Gli3 function causes a vast reduction in the activity of this pathway, shedding light on how the loss of Gli3causes the characteristic structural brain abnormalities at a molecular level, which in turn provides valuable information for understanding the basis of the human syndromes associated with loss of this gene.
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