Dev120220 2521..2532
نویسندگان
چکیده
In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in theSAN.Herewepresent evidence that inmiceShox2 antagonizes the transcriptional output ofNkx2-5 in thePVmyocardium and in a functional Nkx2-5 domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5 domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. ExplantedShox2 cells from the embryonic PVmyocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surroundingShox2− cells.Shox2 deletion led toHcn4 ablation in the developing PVmyocardium.Nkx25hypomorphism rescued the requirement forShox2 for theexpression of genes essential for SAN development in Shox2mutants. Similarly, thepacemaker-like phenotype induced in thePVmyocardium inNkx25 hypomorphs reverted back to aworkingmyocardial phenotypewhen Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.
منابع مشابه
A Bibliography of Papers in Lecture Notes in Computer Science ( 1996 ) , Part 2 of 2
(n− 1) [2526]. (t, n) [2439]. 1/p [1327]. 2 [775, 1963, 1726, 1029, 2713, 2783, 931, 993, 807, 1622, 1907, 813, 2163]. 3 [2532, 1805, 1912, 1026, 445, 1309, 1182, 320, 904, 1029, 1296, 1246, 1257, 1256, 2521, 807, 657, 1796, 1287, 1704, 816, 1791]. 4 [1337, 2534, 791]. 81/2 [945, 950]. t [356]. ax+ b mod p [353, 354]. d [887, 2572]. E [1116]. ` [827]. f [1712]. h [1174]. k [1490, 2604, 1465, 25...
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