Characterization of the Functional Roles of Six2 During Kidney and Stomach Development

A better understanding of the cellular and molecular mechanisms controlling different aspects of normal and pathological organogenesis is central to human health. To this end, the characterization of the functional roles of genes involved in mammalian organogenesis by using gain- and loss-of-function approaches in animal models is a powerful experimental approach. As described in this thesis, I identify the homeobox gene Six2 as an important gene regulating different aspects of kidney and pyloric sphincter formation. The generated Six2-null mouse strain exhibits major phenotypic alterations in the development of these two structures. Homeobox-containing genes have been shown to play key roles in a variety of developmental processes in multicellular organisms. The previously identified Six/so family of homeobox transcription factors in vertebrates includes six members (Six1-Six6). Six2 was found to be expressed in many tissues during murine development including the developing eyes, kidneys, stomach, branchial arches, limb buds, otic and olfactory epithelia, somites, hindbrain, Rathke’s pouch, and genital eminence. The development of many of these organs relies on mesenchymal-epithelial interactions. Mammalian kidney organogenesis is a classical model of branching morphogenesis and reciprocal inductive interactions responsible for mesenchyme-to-epithelia transition. During kidney development, the metanephric mesenchyme responds to inductive signals emanating from the ureteric bud to generate the epithelia of the nephron, the functional excretory unit of the kidney. The metanephric mesenchyme is a multipotent renal progenitor cell population that is continuously replenished during nephron formation. The detailed analysis of the Six2-null kidney described in Chapter 2 allowed us to identify Six2 as a key factor responsible for the maintenance of this undifferentiated mesenchymal population. Furthermore, in Chapter 3 I described an important genetic interaction between Six2 and Wnt9b, a member of the Wnt family of signaling molecules, during kidney organogenesis. In Chapter 4, I investigated the functional role of Six2 during stomach organogenesis, a process that in mammals is poorly understood. I determined that Six2 activity is critical for the formation of the pyloric sphincter, a constriction of the stomach wall that is necessary to prevent intestinal reflux. Together, these results will add to our understanding of the fundamental causes of human developmental disorders such as Branchio-oto-renal syndrome, renal hypodysplasia, and infantile hypertrophic pyloric stenosis in which alterations in the functional activity of SIX2 may play a role.