Ebf3, or Early B-cell Factor 3, is a transcription factor with diverse functions. It is involved in multiple biological processes such as lympho-hematopoiesis, neurodevelopment, and ossification, and is associated with diseases like nasopharyngeal carcinoma, acute myeloid leukemia, and EBF3-related syndromic neurodevelopmental disorder [1,2,3,4,5,6]. In lympho-hematopoiesis, Ebf3+ niche-derived CXCL12 is crucial for the localization and maintenance of hematopoietic stem cells, especially for lymphoid-biased or balanced HSCs [1]. In the context of EBF3-related syndrome, heterozygous mutations or deletions of Ebf3 cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia, often with cerebellar malformation [2]. In nasopharyngeal carcinoma, EBF3 promotes metastasis by upregulating Vimentin [3].

In mouse models, Ebf3 knockout leads to sternum ossification defects due to defective generation of Runx2+ pre-osteoblasts, highlighting its role in the differentiation of lateral plate mesoderm towards osteoblasts forming sternum tissues [6]. In acute myeloid leukemia, Bmal1 inhibits ferroptosis by promoting EZH2-mediated EBF3 methylation, suppressing EBF3 and ALOX15 expression, thus accelerating AML [5]. In Parkinson's disease, EBF3 attenuates the disease by directly regulating CNTNAP4 transcription, and its low expression in the substantia nigra of PD patients may be related to low m6A methylation modification [7].

In conclusion, Ebf3 plays essential roles in various biological processes and is implicated in multiple disease conditions. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into the underlying mechanisms of diseases related to Ebf3, such as neurodevelopmental disorders, leukemia, and cancer metastasis, and potentially guiding the development of novel therapeutic strategies.

References:

1. Nakatani, Taichi, Sugiyama, Tatsuki, Omatsu, Yoshiki, Kondoh, Gen, Nagasawa, Takashi. 2023. Ebf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells. In Nature communications, 14, 6402. doi:10.1038/s41467-023-42047-2. https://pubmed.ncbi.nlm.nih.gov/37880234/

2. Ciaccio, Claudia, Pantaleoni, Chiara, Moscatelli, Marco, Bulgheroni, Sara, D'Arrigo, Stefano. 2023. Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3-Related Syndrome. In Neurology. Genetics, 9, e200049. doi:10.1212/NXG.0000000000200049. https://pubmed.ncbi.nlm.nih.gov/37090941/

3. Ding, Shirong, Wang, Xin, Lv, Dongming, Kang, Tiebang, Xia, Yunfei. 2021. EBF3 reactivation by inhibiting the EGR1/EZH2/HDAC9 complex promotes metastasis via transcriptionally enhancing vimentin in nasopharyngeal carcinoma. In Cancer letters, 527, 49-65. doi:10.1016/j.canlet.2021.12.010. https://pubmed.ncbi.nlm.nih.gov/34906623/

4. Zhu, Jitao, Li, Wenhui, Yu, Sha, Zhou, Shuizhen, Wang, Huijun. 2023. Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients. In Frontiers in pediatrics, 11, 1091532. doi:10.3389/fped.2023.1091532. https://pubmed.ncbi.nlm.nih.gov/36937983/

5. Wang, Dan, Wang, Fenglin, Zhang, Haixia, Chen, Pan, Yang, Minghua. 2023. Circadian clock protein Bmal1 accelerates acute myeloid leukemia by inhibiting ferroptosis through the EBF3/ALOX15 axis. In Cancer science, 114, 3446-3460. doi:10.1111/cas.15875. https://pubmed.ncbi.nlm.nih.gov/37271497/

6. Kuriki, Mao, Sato, Fuminori, Arai, Hiroyuki N, Shukunami, Chisa, Sehara-Fujisawa, Atsuko. 2020. Transient and lineage-restricted requirement of Ebf3 for sternum ossification. In Development (Cambridge, England), 147, . doi:10.1242/dev.186239. https://pubmed.ncbi.nlm.nih.gov/32398354/

7. Hu, Wentao, Wang, Menghan, Sun, Guifang, Zhang, Limin, Lu, Hong. 2024. Early B Cell Factor 3 (EBF3) attenuates Parkinson's disease through directly regulating contactin-associated protein-like 4 (CNTNAP4) transcription: An experimental study. In Cellular signalling, 118, 111139. doi:10.1016/j.cellsig.2024.111139. https://pubmed.ncbi.nlm.nih.gov/38479556/