Development of the Thymus Requires Signaling Through the Fibroblast Growth Factor Receptor R2-IIIb

Abstract

Mice deficient for fibroblast growth factor (Fgf)R2-IIIb show a block in thymic growth after embryonic day 12.5, a stage that just precedes its detection in thymic epithelial cells. Fgf7 and Fgf10, the main ligands for FgfR2-IIIb, are expressed in the mesenchyme surrounding the thymic epithelial primordium, and Fgf10-deficient mice also exhibit impaired thymic growth. Hence, Fgf signaling is essential for thymic epithelial proliferation. In addition to the proliferative block, most thymic epithelial cells fail to progress from an immature cytokeratin 5-positive to a cytokeratin 5-negative phenotype. Nevertheless, sufficient epithelial cell differentiation occurs in the severely hypoplastic thymus to allow the development of CD4/CD8-double-positive thymocytes and a very small number of single-positive thymocytes expressing TCRs.

FGFR2IIIb signaling regulates thymic epithelial differentiation

“…7l,m and 7n,o), indicating that the expanded K5 expression did not reflect an expansion of differentiated medullary TE in the lckFGFR2DN TG thymus. The thymic phenotype of lckFGFR2DN mice hypocellularity, expansion of K5 expression, and normal thymocyte development, recapitulated the major alterations described in neonatal FGFR2IIIb-deficient mice (Revest et al, 2001). …”

“…Finally, expression of a FGFR2DN receptor regulated by the proximal lck promoter resulted in thymic hypoplasia and precocious thymic involution that were associated with altered TE differentiation but a normal pattern of thymocyte development. Although the lckFGFR2DN transgenic mice did allow an assessment of the thymic response of FGFR2DN postnatally and essentially recapitulated the thymic phenotype of FGFR2IIIb-deficient thymus (Revest et al, 2001), we cannot strictly attribute the thymic phenotype to a postnatal response, because proximal lck promoter is active in CD44 ϩ CD25 Ϫ T-cell progenitors which are present in the fetal thymus by approximately 13 days of development. This leaves open the formal possibility that the postnatal thymic phenotype of these mice reflects an irreversible alteration of TE development during fetal development and the postnatal effects that we observed are secondary to a restricted fetal event.…”

“…The proposition that progenitor TE could be a target of FGFR2IIIb signaling has a precedent in the organogenesis of the pancreas, where the mesenchyme surrounding the FGFR2IIIb ϩ endodermal buds destined to become pancreas express FGF10, similar to the relationship between thymic epithelial progenitor endoderm and neural crestderived mesenchyme (Revest et al, 2001;Jenkinson et al, 2003). In FGF10 Ϫ/Ϫ mice, the pancreas is hypoplastic but contains all of the cellular constituents (Bhushan et al, 2001), analogous to the hypoplastic thymus of FGF10R2IIIb/FGF10-deficient mice (Revest et al, 2001) and the lckFGFR2 DN mice described here.…”

“…A subset of the fibroblast growth family, FGF1, FGF3, FGF7 (keratinocyte growth factor; KGF), FGF10, and FGF22 (Umemori et al, 2004) serve as ligands for the IIIb isoform of FGFR2 that is primarily expressed by epithelial cells (reviewed in Powers et al, 2000). Targeted disruption of the FGFR2IIIb gene or expression of a soluble dominant-negative form of this receptor results in a spectrum of developmental defects affecting multiple tissues/organs, including markedly hypoplastic thymi (Celli et al, 1998;De Moerlooze et al, 2000;Revest et al, 2001). Many of the sequelae of FGFR2IIIb deficiency are recapitulated in FGF10-deficient mice (Revest et al, 2001), but not FGF7-deficient mice (Guo et al, 1996), indicating a nonredundant role for FGF10 in these developmental processes.…”

“…Targeted disruption of the FGFR2IIIb gene or expression of a soluble dominant-negative form of this receptor results in a spectrum of developmental defects affecting multiple tissues/organs, including markedly hypoplastic thymi (Celli et al, 1998;De Moerlooze et al, 2000;Revest et al, 2001). Many of the sequelae of FGFR2IIIb deficiency are recapitulated in FGF10-deficient mice (Revest et al, 2001), but not FGF7-deficient mice (Guo et al, 1996), indicating a nonredundant role for FGF10 in these developmental processes.…”