BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cord.
BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cord.
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DOI：
10.1016/j.ydbio.2012.05.014
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发表时间：
2012-07-15
影响因子：
2.7
通讯作者：
Butler SJ
中科院分区：
文献类型：
--
作者：
Hazen VM;Andrews MG;Umans L;Crenshaw EB 3rd;Zwijsen A;Butler SJ
骨形态发生蛋白（BMPs）在发育中的脊髓中具有多种活性：它们指定最背侧神经元群体的身份，然后指导背侧中间神经元（dI）1连合轴突的轨迹。这些活动是如何被背神经元解码以导致不同的细胞结果的？我们以前的研究表明，BMP的多种功能是由BMP受体的经典家族介导的，然后由特异性抑制性（I）Smads调节，其阻断Smad第二信使复合物的活性。然而，这种复合体在多大程度上转化了脊髓中BMP的不同活性仍未得到解决。在这里，我们证明了受体激活的（R）Smads，Smad 1和Smad 5发挥不同的作用，介导骨形成蛋白的能力，直接细胞命运的规范和轴突生长。Smad 1和Smad 5在脊髓内占据空间上不同的隔室，Smad 5主要与神经祖细胞相关，Smad 1与分化的神经元相关。与此表达谱一致，小鼠胚胎功能丧失实验表明，Smad 5是必需的收购背脊髓神经元的身份，而Smad 1是至关重要的dI 1轴突生长的调节。因此，R-Smads，像I-Smads一样，在脊髓中间神经元发育过程中具有介导BMP依赖性细胞过程的独立作用。
Bone Morphogenetic Proteins (BMPs) have multiple activities in the developing spinal cord: they specify the identity of the dorsal-most neuronal populations and then direct the trajectories of dorsal interneuron (dI) 1 commissural axons. How are these activities decoded by dorsal neurons to result in different cellular outcomes? Our previous studies have shown that the diverse functions of the BMPs are mediated by the canonical family of BMP receptors and then regulated by specific inhibitory (I) Smads, which block the activity of a complex of Smad second messengers. However, the extent to which this complex translates the different activities of the BMPs in the spinal cord has remained unresolved. Here, we demonstrate that the receptor-activated (R) Smads, Smad1 and Smad5 play distinct roles mediating the abilities of the BMPs to direct cell fate specification and axon outgrowth. Smad1 and Smad5 occupy spatially distinct compartments within the spinal cord, with Smad5 primarily associated with neural progenitors and Smad1 with differentiated neurons. Consistent with this expression profile, loss of function experiments in mouse embryos reveal that Smad5 is required for the acquisition of dorsal spinal neuron identities whereas Smad1 is critical for the regulation of dI1 axon outgrowth. Thus the R-Smads, like the I-Smads, have discrete roles mediating BMP-dependent cellular processes during spinal interneuron development.
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