BMPs are direct triggers of interdigital programmed cell death.
BMPs are direct triggers of interdigital programmed cell death.
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DOI：
10.1016/j.ydbio.2015.12.016
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发表时间：
2016-03-15
影响因子：
2.7
通讯作者：
Lewandoski M
中科院分区：
文献类型：
--
作者：
Kaltcheva MM;Anderson MJ;Harfe BD;Lewandoski M
在脊椎动物胚胎发生过程中，趾间间充质通过程序性细胞死亡（PCD）而被去除，除了具有蹼状肢的物种。尽管人们早已知道骨形态发生蛋白（BMPs）在这一过程中发挥作用，但尚不清楚它们是否在趾间充质中发挥直接作用，或者是否仅通过影响成纤维细胞生长因子（FGF）信号传导间接发挥作用。一系列遗传学研究表明，BMP通过调节FGF活性从顶端外胚层嵴（AER）的撤回而间接起作用;这种FGF活性作为底层间充质的细胞存活因子。其他研究使用外源性因子抑制BMP活性在断肢小鼠提示BMP不直接作用于间充质。为了解决BMP是否直接起作用的问题，我们使用了一种叉指特异性Cre系来抑制编码BMP信号通路组分的几个基因，而不干扰AER-FGF活性的正常下调。在趾间充质中表达的三种Bmp中，Bmp 7是PCD所必需的，但Bmp 2和Bmp 4都具有冗余作用，其中Bmp 2是更突出的参与者。通过删除受体基因Bmpr 1a将BMP信号去除到趾间，导致PCD和并指缺失，从而明确证明BMP是该组织中PCD的直接触发因素。我们提出了一个模型，其中两个事件必须发生正常的指间PCD：BMP死亡触发器的存在和FGF生存活性的情况下。我们证明，这两个事件都不是指间脉管系统的形成所必需的，这是必要的PCD。然而，这两个事件都集中在激活PCD的活性氧物质的产生上。
During vertebrate embryogenesis the interdigital mesenchyme is removed by programmed cell death (PCD), except in species with webbed limbs. Although bone morphogenetic proteins (BMPs) have long been known to be players in this process, it is unclear if they play a direct role in the interdigital mesenchyme or if they only act indirectly, by affecting fibroblast growth factor (FGF) signaling. A series of genetic studies have shown that BMPs act indirectly by regulating the withdrawal of FGF activity from the apical ectodermal ridge (AER); this FGF activity acts as a cell survival factor for the underlying mesenchyme. Other studies using exogenous factors to inhibit BMP activity in explanted mouse limbs suggest that BMPs do not act directly in the mesenchyme. To address the question of whether BMPs act directly, we used an interdigit-specific Cre line to inactivate several genes that encode components of the BMP signaling pathway, without perturbing the normal downregulation of AER-FGF activity. Of three Bmps expressed in the interdigital mesenchyme, Bmp7 is necessary for PCD, but Bmp2 and Bmp4 both have redundant roles, with Bmp2 being the more prominent player. Removing BMP signals to the interdigit by deleting the receptor gene, Bmpr1a, causes a loss of PCD and syndactyly, thereby unequivocally proving that BMPs are direct triggers of PCD in this tissue. We present a model in which two events must occur for normal interdigital PCD: the presence of a BMP death trigger and the absence of an FGF survival activity. We demonstrate that neither event is required for formation of the interdigital vasculature, which is necessary for PCD. However, both events converge on the production of reactive oxygen species that activate PCD.
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影响因子：
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