Regulation of Pharyngeal Region Patterning and Organogenesis by Sonic Hedgehog

Abstract

Patterning of the pharyngeal region determines the proper development of multiple organs in addition to structures of the face, head and neck. The thymus and parathyroid originate from the third pharyngeal pouch and regulate the development of the immune system and calcium homeostasis, respectively. Although functionally these organs are in no way similar, they are derived from a common endodermal primordium, which develops around E l 1.0-El 1.5 in the mouse. At this stage it is apparent that the rudiment has regionalized into the parathyroid and thymus specific domains. Sonic hedgehog (Shh) is a secreted molecule that contributes to the patterning and regionalization of multiple tissues throughout embryonic development. As a morphogen, Shh initially specifies heterogeneous cell types within a field of cells, regionalizing the target tissue into functional domains. Shh activity can also regulate the proliferation and/or survival of those same cells continuing to contribute to the development of the tissue both morphologically and functionally. Since Shh expression is present in the pharyngeal endoderm, it was a promising candidate for patterning of the pharyngeal region as well as the regionalization of the common parathyroid/thymus primordium. Since die pharyngeal region is a specialized vertebrate structure from which several endocrine organs are derived, correct patterning of the pharyngeal region is important for these organs to initiate and develop properly. Our analysis of the Shh'A mutant has revealed multiple organ phenotypes which are die result of die necessity for Shh signaling at multiple stages of development in the pharyngeal region. These include loss of pharyngeal pouch identity, atrophy of the first pharyngeal arch, parathyroid agenesis, dysmorphic and ectopic growth of the thyroid; and thymic hypoplasia and improper differentiation of the thymic epithelial cell microenvironment. This dissertation is a description of our analysis of the early patterning and organogenesis phenotypes of the Shh'A mutant. Based on these data we propose a model describing the Shh-dependent mechanisms that regulate these events in the mid-gestation staged mouse embryo.