Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12

Proliferation is tightly regulated during T cell development and is limited to immature CD4(−)CD8(−) thymocytes. The major proliferative event is initiated at the ‘β-selection’ stage following successful rearrangement of Tcrβ and is triggered by and dependent on concurrent signaling by Notch and the pre-TCR; however, it is unclear how these signals cooperate to promote cell proliferation. Here we found that β-selection-associated proliferation required the combined activity of two SCF ubiquitin ligase complexes that included as substrate recognition subunits the F-box proteins Fbxl1 or Fbxl12. Both SCF complexes targeted the cyclin-dependent kinase inhibitor Cdkn1b for ubiquitinylaton and degradation. We found that Notch signals induced the transcription of Fbxl1 whereas pre-TCR signals induced the transcription of Fbxl12. Thus, concurrent Notch and pre-TCR signaling induced the expression of two genes, Fbxl1 and Fbxl12, whose products functioned identically but additively to promote degradation of Cdkn1b, cell cycle progression, and proliferation of β-selected thymocytes.