Elevated levels of Wnt signaling disrupt thymus morphogenesis and function

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.

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

“…Based on flow cytometry and TF binding site analyses, we found that PSMB11 preserved the integrity of the cTEC-specific transcriptome by inhibiting WNT signaling via degradation of b-catenin. This conclusion is consistent with the observation that constitutive WNT activation in TECs disrupts their function and skews cTECs toward an mTEC phenotype (37). The sole difference between immunoproteasomes (found in mTECs) and thymoproteasomes (present in cTECs) is the nature of their chymotryptic catalytic subunit: PSMB8 in immunoproteasomes and PSMB11 in thymoproteasomes.…”

“…Moreover, they strongly suggest that enhanced WNT signaling is instrumental in the acquisition of mTEC features by Psmb11 2/2 cTECs. WNT signaling is normally repressed in cTECs (in contrast to thymocytes), and upon overactivation of WNT signaling, cTECs acquire features of mTECs (36,37). The key switch in the canonical WNT pathway is the cytoplasmic protein b-catenin, whose abundance is regulated by proteasomal degradation (36).…”

Epithelial Development Based on a Branching Morphogenesis Program: The Special Condition of Thymic Epithelium

“…However, recent results indicate that a proper thymus development can only occur when β-catenin-dependent Wnt signaling is low or lacking [133]. Thus, β-catenin-deficient thymi exhibit Foxn1 expression, and stabilized β-catenin overexpression shows decreased rather than increased Foxn1 transcripts [133,134]. Therefore, these results suggest that β-catenin is dispensable for Foxn1 expression in fetal TECs.…”

“…Thus, overexpression of Dkk1, a Wnt4 inhibitor, in TECs induces thymic atrophy with reduced epithelial progenitors and TEC proliferation and appearance of TEC proliferation [132]. However, recent results indicate that a proper thymus development can only occur when β-catenin-dependent Wnt signaling is low or lacking [133]. Thus, β-catenin-deficient thymi exhibit Foxn1 expression, and stabilized β-catenin overexpression shows decreased rather than increased Foxn1 transcripts [133,134].…”

“…However, it is important to remark that sustained Wnt signaling promotes the production of secreted Wnt antagonisms [136] that block thymocyte development in FTOCs [137]. On the other hand, other signaling pathways involved in TEC differentiation, such as those mediated by BMPs, modulate the effects produced by Wnt4 overexpression [133].…”