Banerji Rajeswari, Eble Diane M, Iovine M Kathryn, Skibbens Robert V
Department of Biological Science, Lehigh University, Bethlehem, Pennsylvania.
Dev Dyn. 2016 Jan;245(1):7-21. doi: 10.1002/dvdy.24354. Epub 2015 Nov 25.
Roberts syndrome (RBS) is a rare genetic disorder characterized by craniofacial abnormalities, limb malformation, and often severe mental retardation. RBS arises from mutations in ESCO2 that encodes an acetyltransferase and modifies the cohesin subunit SMC3. Mutations in SCC2/NIPBL (encodes a cohesin loader), SMC3 or other cohesin genes (SMC1, RAD21/MCD1) give rise to a related developmental malady termed Cornelia de Lange syndrome (CdLS). RBS and CdLS exhibit overlapping phenotypes, but RBS is thought to arise through mitotic failure and limited progenitor cell proliferation while CdLS arises through transcriptional dysregulation. Here, we use the zebrafish regenerating fin model to test the mechanism through which RBS-type phenotypes arise.
esco2 is up-regulated during fin regeneration and specifically within the blastema. esco2 knockdown adversely affects both tissue and bone growth in regenerating fins-consistent with a role in skeletal morphogenesis. esco2-knockdown significantly diminishes cx43/gja1 expression which encodes the gap junction connexin subunit required for cell-cell communication. cx43 mutations cause the short fin (sof(b123) ) phenotype in zebrafish and oculodentodigital dysplasia (ODDD) in humans. Importantly, miR-133-dependent cx43 overexpression rescues esco2-dependent growth defects.
These results conceptually link ODDD to cohesinopathies and provide evidence that ESCO2 may play a transcriptional role critical for human development.
罗伯茨综合征（RBS）是一种罕见的遗传性疾病，其特征为颅面异常、肢体畸形，且常伴有严重智力障碍。RBS由ESCO2基因突变引起，ESCO2编码一种乙酰转移酶，可修饰黏连蛋白亚基SMC3。SCC2/NIPBL（编码一种黏连蛋白装载蛋白）、SMC3或其他黏连蛋白基因（SMC1、RAD21/MCD1）的突变会导致一种相关的发育障碍，称为科妮莉亚·德·朗格综合征（CdLS）。RBS和CdLS表现出重叠的表型，但RBS被认为是通过有丝分裂失败和有限的祖细胞增殖产生的，而CdLS是通过转录失调产生的。在此，我们使用斑马鱼再生鳍模型来测试RBS型表型产生的机制。
在鳍再生过程中，尤其是在再生芽基内，esco2表达上调。esco2基因敲低对再生鳍中的组织和骨骼生长均产生不利影响，这与它在骨骼形态发生中的作用一致。esco2基因敲低显著降低了cx43/gja1的表达，cx43/gja1编码细胞间通讯所需的间隙连接连接蛋白亚基。cx43突变会导致斑马鱼出现短鳍（sof(b123)）表型以及人类出现眼齿指发育异常（ODDD）。重要的是，miR-133依赖的cx43过表达可挽救esco2依赖的生长缺陷。
这些结果从概念上将ODDD与黏连蛋白病联系起来，并提供了证据表明ESCO2可能在人类发育中发挥关键的转录作用。
