The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Shandong University, 250012, Jinan, China.
School of Life Sciences, Shandong University, 266237, Qingdao, China.
Cell Death Dis. 2019 May 17;10(6):388. doi: 10.1038/s41419-019-1629-7.
CUL4A and CUL4B are closely related members in Cullin family and can each assemble a Cullin-RING E3 ligase complex (Cullin-RING Ligase 4A or 4B, CRL4A, or CRL4B) and participate in a variety of biological processes. Previously we showed that zebrafish cul4a, but not cul4b, is essential for cardiac and pectoral fin development. Here, we have identified cul4a as a crucial regulator of primitive erythropoiesis in zebrafish embryonic development. Depletion of cul4a resulted in a striking reduction of erythroid cells due to the inhibition of erythroid differentiation. Transcript levels for early hematopoietic regulatory genes including scl, lmo2, and gata1 are significantly reduced in cul4a-deficient embryos. Mechanistically, we demonstrated that scl and gata1, the central regulators of primitive hematopoiesis for erythroid determination, are transcriptionally upregulated by cul4a. These findings demonstrate an important role for cul4a in primitive erythropoiesis and may bear implications in regeneration medicine of anemia and related diseases.
CUL4A 和 CUL4B 是 Cullin 家族中密切相关的成员，它们各自可以组装 Cullin-RING E3 连接酶复合物（Cullin-RING Ligase 4A 或 4B、CRL4A 或 CRL4B）并参与多种生物学过程。之前我们已经表明，斑马鱼 cul4a 但不是 cul4b 对于心脏和胸鳍的发育是必不可少的。在这里，我们发现 cul4a 是斑马鱼胚胎发育中原始红细胞生成的关键调节因子。由于红细胞分化受到抑制，cul4a 的缺失导致红细胞数量显著减少。cul4a 缺陷胚胎中早期造血调节基因（包括 scl、lmo2 和 gata1）的转录水平显著降低。在机制上，我们证明了 scl 和 gata1，即红细胞决定的原始造血的中心调节因子，由 cul4a 转录上调。这些发现表明 cul4a 在原始红细胞生成中起着重要作用，这可能对贫血和相关疾病的再生医学具有重要意义。
