Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning.
Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning.
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DOI：
10.1002/dvg.23021
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Clouthier DE
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文献类型：
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作者：
Iklé JM;Tavares AL;King M;Ding H;Colombo S;Firulli BA;Firulli AB;Targoff KL;Yelon D;Clouthier DE
在颌口动物中，咽弓内神经脊细胞(NCC)的背腹(D-V)构型对铰接性颌骨的发育至关重要。调节这一过程的关键信号之一是内皮素-1(EDN1)。EDN1与Endothelin-A受体(Ednra)结合的丢失会导致Ednra信号的丢失，从而导致人类、小鼠和斑马鱼的面部出生缺陷。在这个关键的信号通路中，一个限速步骤是由内皮素转换酶-1(ECE1)将未成熟的EDN1转化为成熟的活性形式。然而，令人惊讶的是，关于Ece1转录是如何被诱导或调控的，人们知之甚少。我们在这里证明了NKX2.5是斑马鱼正常头面部发育所必需的，并部分通过上调ece1的表达来发挥作用。斑马鱼胚胎中NKX2.5基因的中断导致腹侧和背侧咽弓衍生元件的缺陷，腹侧ARCH基因表达的变化与Ednra信号的中断一致。ECE1mRNA挽救了NKX2.5的突变表型，表明NKX2.5通过调节Ece1的表达或功能发挥作用。这些研究展示了NKX2.5在胚胎发育中的新功能，并为探索人类面部疾病潜在的机制提供了新的途径。
In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediates this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.