| First Author | Okuyama K | Year | 2024 |
| Journal | Nat Immunol | Volume | 25 |
| Issue | 12 | Pages | 2284-2296 |
| PubMed ID | 39487351 | Mgi Jnum | J:360845 |
| Mgi Id | MGI:7850856 | Doi | 10.1038/s41590-024-01997-5 |
| Citation | Okuyama K, et al. (2024) A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development. Nat Immunol 25(12):2284-2296 |
| abstractText | Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B(N441K), was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b(N440K) mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46(+) cells in the thymus and reduction in TBR1(+) neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11b(N440K) mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins. |
