Titus Tom A, Yan Yi-Lin, Wilson Catherine, Starks Amber M, Frohnmayer Jonathan D, Bremiller Ruth A, Cañestro Cristian, Rodriguez-Mari Adriana, He Xinjun, Postlethwait John H
Institute of Neuroscience, University of Oregon, 1425 E. 13th Avenue, Eugene, OR 97403, USA.
Mutat Res. 2009 Jul 31;668(1-2):117-32. doi: 10.1016/j.mrfmmm.2008.11.017. Epub 2008 Dec 3.
Fanconi anemia (FA) is a genetic disease resulting in bone marrow failure, high cancer risks, and infertility, and developmental anomalies including microphthalmia, microcephaly, hypoplastic radius and thumb. Here we present cDNA sequences, genetic mapping, and genomic analyses for the four previously undescribed zebrafish FA genes (fanci, fancj, fancm, and fancn), and show that they reverted to single copy after the teleost genome duplication. We tested the hypothesis that FA genes are expressed during embryonic development in tissues that are disrupted in human patients by investigating fanc gene expression patterns. We found fanc gene maternal message, which can provide Fanc proteins to repair DNA damage encountered in rapid cleavage divisions. Zygotic expression was broad but especially strong in eyes, central nervous system and hematopoietic tissues. In the pectoral fin bud at hatching, fanc genes were expressed specifically in the apical ectodermal ridge, a signaling center for fin/limb development that may be relevant to the radius/thumb anomaly of FA patients. Hatching embryos expressed fanc genes strongly in the oral epithelium, a site of squamous cell carcinomas in FA patients. Larval and adult zebrafish expressed fanc genes in proliferative regions of the brain, which may be related to microcephaly in FA. Mature ovaries and testes expressed fanc genes in specific stages of oocyte and spermatocyte development, which may be related to DNA repair during homologous recombination in meiosis and to infertility in human patients. The intestine strongly expressed some fanc genes specifically in proliferative zones. Our results show that zebrafish has a complete complement of fanc genes in single copy and that these genes are expressed in zebrafish embryos and adults in proliferative tissues that are often affected in FA patients. These results support the notion that zebrafish offers an attractive experimental system to help unravel mechanisms relevant not only to FA, but also to breast cancer, given the involvement of fancj (brip1), fancn (palb2) and fancd1 (brca2) in both conditions.
范可尼贫血（FA）是一种遗传性疾病，可导致骨髓衰竭、高癌症风险和不育，以及包括小眼症、小头畸形、桡骨发育不全和拇指发育异常在内的发育异常。在此，我们展示了四个此前未描述的斑马鱼FA基因（fanci、fancj、fancm和fancn）的cDNA序列、遗传图谱和基因组分析，并表明它们在硬骨鱼基因组复制后恢复为单拷贝。我们通过研究fanc基因表达模式，检验了FA基因在胚胎发育过程中在人类患者中受影响的组织中表达这一假设。我们发现了fanc基因的母源信息，其可提供Fanc蛋白以修复快速卵裂期遇到的DNA损伤。合子表达广泛，但在眼睛、中枢神经系统和造血组织中尤其强烈。在孵化时的胸鳍芽中，fanc基因特异性地在顶端外胚层嵴中表达，顶端外胚层嵴是鳍/肢体发育的信号中心，可能与FA患者的桡骨/拇指异常有关。孵化胚胎在口腔上皮中强烈表达fanc基因，口腔上皮是FA患者鳞状细胞癌的发生部位。幼体和成体斑马鱼在大脑的增殖区域表达fanc基因，这可能与FA患者的小头畸形有关。成熟的卵巢和睾丸在卵母细胞和精母细胞发育的特定阶段表达fanc基因，这可能与减数分裂中同源重组期间的DNA修复以及人类患者的不育有关。肠道在增殖区强烈且特异性地表达一些fanc基因。我们的结果表明，斑马鱼拥有完整的单拷贝fanc基因，且这些基因在斑马鱼胚胎和成体的增殖组织中表达，而这些组织在FA患者中常受影响。这些结果支持了这样一种观点，即斑马鱼提供了一个有吸引力的实验系统，不仅有助于揭示与FA相关的机制，还能揭示与乳腺癌相关的机制，因为fancj（brip1）、fancn（palb2）和fancd（brca2）在这两种疾病中都有涉及。
