Hedgehog Signaling Regulates Differentiation from Double-Negative to Double-Positive Thymocyte

Abstract

The hedgehog (Hh) signaling pathway is involved in the development of many tissues. Here we show that sonic hedgehog (Shh) is involved in thymocyte development. Our data suggest that termination of Hh signaling is necessary for differentiation from CD4-CD8-double-negative (DN) to CD4+CD8+ double-positive (DP) thymocyte. Shh is produced by the thymic stroma, and Patched and Smoothened (Smo), the transmembrane receptors for Shh, are expressed in DN thymocytes. A neutralizing monoclonal antibody against Shh increases differentiation of DN to DP thymocytes, and Shh protein arrests thymocyte differentiation at the CD25+ DN stage, after T cell receptor beta (TCRbeta) gene rearrangement. We show that one consequence of pre-TCR signaling is downregulation of Smo, allowing DN thymocytes to proliferate and differentiate.

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

“…In the thymus, SHH is a regulator of T-cell differentiation and T-cell receptor repertoire selection. 4,21,22 In lymph nodes, Sacedon et al 4 found that SHH is produced by follicular dendritic cells and that germinal center B cells express PTCH and SMO, components of the SHH receptor, suggesting that germinal center B cells are targets of SHH ligand produced by follicular dendritic cells. These authors also showed in vitro that SHH inhibition induces apoptosis in germinal center B cells, and that addition of exogenous SHH rescues germinal center B cells from Fas-induced apoptosis.…”

Bone Morphogenetic Protein 2/4 Signaling Regulates Early Thymocyte Differentiation

“…Both TGF␤ and sonic hedgehog (Shh) negatively regulate thymocyte development and inhibit the transition from DN to DP cell (24,42). Shh arrests thymocyte development at the CD25 ϩ DN stage, after TCR␤ gene rearrangement (24), whereas BMP4 treatment arrests thymocyte development at the earliest CD44 ϩ CD25 Ϫ DN stage.…”

“…Shh arrests thymocyte development at the CD25 ϩ DN stage, after TCR␤ gene rearrangement (24), whereas BMP4 treatment arrests thymocyte development at the earliest CD44 ϩ CD25 Ϫ DN stage. The Shh and BMP4 pathways interact during the organization of many developing tissues, and in human hemopoietic precursors the Shh pathway is upstream of BMP4 signaling (21).…”

“…Mouse Tsg is expressed during lymphocyte development (22), and Chordin (23), BMP4 (24), and the Smad-interacting transcription factor Schnurri-2 (25) are expressed in the mouse thymus, suggesting that BMP signaling may play a role in thymocyte development.…”

Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID–ß2m–/– repopulating cells.

“…Furthermore, the receptor-complex proteins Ptc and Smo were expressed in the human primary and hTERT stromal cells ( Figure 1C). We also examined the expression of Shh, which is involved in the development of neural and thymic tissues during embryogenesis 19,30 and has been reported to enhance ex vivo expansion of HSCs. 20 However, the expression of Shh was not detectable in either primary or hTERT stromal cells, although its expression was easily detected in thymus and HUVECs (data not shown).…”