Abstract
All vertebrates possess a thymus, whose epithelial microenvironment is essential for T cell development and maturation. Despite the importance of the thymus for cellular immune defense, many questions surrounding its morphogenesis remain unanswered. Here, we demonstrate that, in contrast to the situation in many other epithelial cell types, differentiation of thymic epithelial cells (TECs) proceeds normally in the absence of canonical Wnt signaling and the classical adhesion molecule E-cadherin. By contrast, TEC-intrinsic activation of β-catenin-dependent Wnt signaling blocks the morphogenesis of the thymus, and overexpression of a secreted Wnt ligand by TECs dominantly modifies the morphogenesis not only of the thymus, but also of the parathyroid and thyroid. These observations indicate that Wnt signaling activity in the thymus needs to be precisely controlled to support normal TEC differentiation, and suggest possible mechanisms underlying anatomical variations of the thymus, parathyroid and thyroid in humans.
Highlights
The epithelial microenvironment of the thymus exhibits a unique cellular architecture, which strains the standard definitions of epithelial structures, both in anatomy and function
Previous studies demonstrated that E-cadherin is expressed by TECs27, and that blocking homotypic E-cadherin interactions prevents thymic lobe formation in re-aggregate thymus organ culture (RTOC) assays[28], suggesting a functional role in thymus organogenesis
Despite high expression levels of canonical Wnts in the thymus, canonical Wnt signaling to the nucleus appears to be low, when examined by a transgenic reporter (BATgal42); this outcome is in contrast to the situation in the Foxn1-expressing whisker follicle, where the activity of the reporter is high (Fig. 1A)
Summary
The epithelial microenvironment of the thymus exhibits a unique cellular architecture, which strains the standard definitions of epithelial structures, both in anatomy and function. The 3PP forms at around embryonic day 10.5 (E10.5); it consists of a simple endodermal cell layer divided into two domains, each fated to become the epithelial component of either the thymus or the parathyroid. These domains can be identified by the expression of two key transcription factors, Gcm[2] and Foxn[13]. Gcm[2] begins to be expressed at ≈E10.5 in the epithelial cells located in the anterior-dorsal region of the pouch and specifies a parathyroid fate, while Foxn[1] is expressed slightly later at ≈E11.0 in the epithelial cells of the posterior-ventral region of the pouch, and specifies the adoption of a thymic fate. Β-catenin (encoded by the Ctnnb[1] gene), a critical binding partner of E-cadherin has been implicated in thymus development[29]
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