前蛋白转化酶枯草杆菌蛋白酶/kexin5型(Pcsk5)的缺失导致多种发育异常,包括心脏畸形,尾部回归,骶骨前肿块,肾发育不全,前后图案缺损,气管食管和肛门直肠畸形,并且是VACTERL/尾回归/Currarino综合征的模型(VACTERL关联-椎体异常,肛门闭锁,心脏缺陷,气管食管瘘和/或食管闭锁,肾脏和放射状异常和肢体缺陷)。
使用磁共振成像(MRI),我们检查了具有Pcsk5合子和心脏特异性缺失的小鼠胚胎中的心脏发育。我们表明,除气管食管畸形外,所有表皮谱系中Pcsk5的条件性缺失都可以概括所有发育畸形。使用条件删除策略,我们发现颅心中胚层对Pcsk5有必要和具体的要求,但不适用于截肢间隔或胚胎发育的任何其他方面。令人惊讶的是,从颅心脏中胚层形成的心源性或咽部中胚层祖细胞中Pcsk5的缺失不会影响心脏发育。Pcsk5在神经c中也不是必需的,导致截肢间隔。
我们的结果表明,Pcsk5可能在心脏发育的颅心中胚层中具有重要的早期作用。或者,Pcsk5可能仍然在表达Nkx2.5的心脏祖细胞中发挥关键作用,mRNA或蛋白质的持久性说明缺失对心脏发育的影响。
Loss of proprotein convertase subtilisin/kexin type 5 (
Pcsk5) results in multiple developmental anomalies including cardiac malformations, caudal regression, pre-sacral mass, renal agenesis, anteroposterior patterning defects, and tracheo-oesophageal and anorectal malformations, and is a model for VACTERL/caudal regression/Currarino syndromes (VACTERL association - Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects).
Using magnetic resonance imaging (MRI), we examined heart development in mouse embryos with zygotic and cardiac specific deletion of
Pcsk5. We show that conditional deletion of
Pcsk5 in all epiblastic lineages recapitulates all developmental malformations except for tracheo-esophageal malformations. Using a conditional deletion strategy, we find that there is an essential and specific requirement for Pcsk5 in the cranio-cardiac mesoderm for cardiogenesis, but not for conotruncal septation or any other aspect of embryonic development. Surprisingly, deletion of Pcsk5 in cardiogenic or pharyngeal mesodermal progenitors that form later from the cranio-cardiac mesoderm does not affect heart development. Neither is
Pcsk5 essential in the neural crest, which drives conotruncal septation.
Our results suggest that Pcsk5 may have an essential and early role in the cranio-cardiac mesoderm for heart development. Alternatively, it is possible that
Pcsk5 may still play a critical role in Nkx2.5-expressing cardiac progenitors, with persistence of mRNA or protein accounting for the lack of effect of deletion on heart development.