Gain-of-function induced defects by PITX2 in eye and limb development

Sammanfattning: My research has been focused on eye and limb development with regard to the transcription factor PITX2. In the first paper we present an Axenfeld-Rieger syndrome PITX2 gain-of-function eye mouse model. Axenfeld-Rieger syndrome is a rare autosomal disorder affecting the development of eyes, teeth and abdomen. The eye defects consist of anomalies in the anterior segment. In addition, almost 50% of Axenfeld-Rieger syndrome patients develop glaucoma, the leading cause of vision loss worldwide. The mouse model faithfully recapitulated these eye symptoms. The next paper describes a forelimb phenotype due to a brief pulse of PITX2 overexpression in the forelimbs during embryogenesis. This overexpression interferes with tendon morphogenesis resulting in severe bone malformations, which in turn twist the forelimb and makes it non-supportable. The mechanisms behind limb tendon development and positioning are largely unknown, which makes this study a valuable resource for further studies on the development of the musculoskeletal system. In the third paper we compare the phenotypic outcome of PITX2 overexpression between three different mouse strains to study the effect of strain specific modifier genes. We observe both gain-of- and loss-of-function phenotypes, which indicate existence of strain specific genes working in concert with PITX2 during eye and limb development. To put these papers in a context I have aimed at gaining a deeper insight into the role of PITX2 in the development of eye and limb, and to increase the understanding of the pathophysiology of the eye defects associated with Axenfeld-Rieger syndrome.