Sox6 regulation of cardiac myocyte development
Sox6 regulation of cardiac myocyte development
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DOI：
10.1093/nar/gkg807
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发表时间：
2003-10-15
影响因子：
14.9
通讯作者：
Brilliant, MH
中科院分区：
文献类型：
--
作者：
Cohen-Barak, O;Yi, ZH;Brilliant, MH
已经鉴定出与心脏骨骼肌病、心脏传导阻滞、生长延迟和出生后早期死亡相关的小鼠突变（p（100 H）/p（100 H））。在该突变中被破坏的基因编码转录因子Sox 6。P19 CL 6细胞被用作体外心肌细胞分化系统，并且揭示了当细胞致力于分化为跳动的心肌细胞时，Sox 6仅表达。我们使用酵母双杂交系统来鉴定Prtb（Proline-rich transcript of the brain）蛋白作为Sox 6相互作用物，随后通过免疫共沉淀证实了相互作用。P19 CL 6细胞中Prtb的表达随着向搏动心肌细胞分化而增加。使用稳定转染有BMP（骨形态发生蛋白）拮抗剂noggin的P19 CL 6细胞，我们发现BMP表达是心肌细胞分化中Sox 6表达所必需的。令人惊讶的是，在P19 CL 6细胞分化为搏动心肌细胞时，L型钙通道α（1c）亚基基因的表达降低。在P19 CL 6细胞中单独异位表达Sox 6或Prtb导致L型Ca 2 + α（1c）表达下调，但当Sox 6和Prtb共转染到细胞中时，L型Ca 2 + α（1c）保持在基础水平。在体内观察到Sox 6和L型Ca 2 + α（1c）表达的类似关系（比较野生型和p（100 H）/p（100 H）突变小鼠）。因此，Sox 6在心脏分化中的BMP通路内，与Prtb相互作用，并且可能在心脏L型Ca 2+通道的调节中发挥关键作用。
A mouse mutation (p(100H)/p(100H)) has been identified that is associated with cardioskeletal myopathy, heart block, delayed growth and early postnatal death. The gene that is disrupted in this mutation encodes the transcription factor Sox6. P19CL6 cells were used as an in vitro cardiomyocyte differentiation system and revealed that Sox6 is expressed exclusively when the cells are committed to differentiate to beating cardiac myocytes. We used the yeast two-hybrid system to identify the Prtb (Proline-rich transcript of the brain) protein as a Sox6 interactor, and subsequently confirmed the interaction by co-immunoprecipitation. Prtb expression in P19CL6 cells increased with differentiation to beating cardiomyocytes. Using the P19CL6 cells stably transfected with noggin, an antagonist of BMP (Bone Morphogenic Protein), we found that BMP expression is required for Sox6 expression in cardiomyocyte differentiation. Surprisingly, the expression of the alpha(1c)-subunit gene of the L-type Ca2+ channel decreased in P19CL6 cells as they differentiated to beating cardiac cells. Ectopic expression of Sox6 or Prtb alone in P19CL6 cells caused down-regulation of L-type Ca2+ alpha(1c) expression, but when Sox6 and Prtb were co-transfected to the cells, L-type Ca2+ alpha(1c) remained at basal levels. A similar relationship of Sox6 and L-type Ca2+ alpha(1c) expression was seen in vivo (comparing wild-type and p(100H)/p(100H) mutant mice). Thus, Sox6 is within the BMP pathway in cardiac differentiation, interacts with Prtb and may play a critical role in the regulation of a cardiac L-type Ca2+ channel.