The Role of Shox2 in SAN Development and Function
The Role of Shox2 in SAN Development and Function
复制标题
Shox2在SAN开发和功能中的作用
DOI：
10.1007/s00246-012-0179-x
复制
发表时间：
2012-08-01
影响因子：
1.6
通讯作者：
Chen, YiPing
中科院分区：
文献类型：
--
作者：
Liu, Hongbing;Espinoza-Lewis, Ramon A.;Chen, YiPing
胚胎发育是一个严格调控的过程，许多基因家族的功能提供了一个调控遗传网络来实现这样的程序。同源异型盒基因是一个广泛的家族，其编码具有特征性的60个氨基酸同源结构域的转录因子。这些基因或编码蛋白质的突变可能导致结构畸形、生理缺陷，甚至胚胎死亡。在Turner综合征和/或Leri-Weill软骨发育不良患者中观察到，身材矮小同源框基因（SHOX）突变与人类特发性身材矮小相关。一个密切相关的人类同源物，SHOX 2，到目前为止还没有与任何综合征或缺陷有关。在小鼠中，SHOX直系同源基因不存在于基因组中;然而，已经鉴定出真正的SHOX 2直系同源基因。对Shox 2基因敲除小鼠模型的分析显示了胚胎发育过程中的关键功能，包括肢体骨骼发育、腭发育、颞下颌关节形成和心血管发育。在胚胎心脏发育过程中，Shox 2仅在静脉窦区域表达，包括窦房结（SAN）和窦瓣。Shox 2无效突变体由于心血管缺陷而具有胚胎致死性，包括严重发育不良的SAN和窦瓣，这归因于除了异常低心率（心动过缓）之外的细胞增殖水平显著降低。此外，已经证明Shox 2通过抑制Nkx2.5来调节遗传网络以维持SAN命运，因此在其正确形成和分化中起重要作用。
Embryonic development is a tightly regulated process, and many families of genes functions to provide a regulatory genetic network to achieve such a program. The homeobox genes are an extensive family that encodes transcription factors with a characteristic 60-amino acid homeodomain. Mutations in these genes or in the encoded proteins might result in structural malformations, physiological defects, and even embryonic death. Mutations in the short-stature homeobox gene (SHOX) is associated with idiopathic short stature in humans, as observed in patients with Turner syndrome and/or Leri-Weill dyschondrosteosis. A closely related human homolog, SHOX2, has not been linked to any syndrome or defect so far. In mice, a SHOX ortholog gene is not present in the genome; however, a true SHOX2 ortholog has been identified. Analyses of Shox2 knockout mouse models have showed crucial functions during embryonic development, including limb skeletogenesis, palatogenesis, temporomandibular joint formation, and cardiovascular development. During embryonic cardiac development, Shox2 is restrictedly expressed in the sinus venosus region, including the sinoatrial node (SAN) and the sinus valves. Shox2 null mutant is embryonically lethal due to cardiovascular defects, including a severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation in addition to an abnormal low heartbeat rate (bradycardia). In addition, it has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the SAN fate and thus plays essential roles in its proper formation and differentiation.