Smilow Neuroscience Program, Department of Physiology and Neuroscience, Howard Hughes Medical Institute, NYU School of Medicine, New York, New York, USA.
PLoS Genet. 2013;9(1):e1003184. doi: 10.1371/journal.pgen.1003184. Epub 2013 Jan 24.
A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5-Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus.
在控制四足动物运动的神经回路组装过程中，一个关键步骤是 lateral motor column（LMC）的指定，这是一个针对肢体肌肉的多样化运动神经元群体。Hox6 基因家族的基因已被认为是脊髓前肢水平 LMC 命运的关键决定因素，其通过促进 LMC 受限基因 Foxp1 和 Raldh2 的表达以及通过排除 Hoxc9 来抑制胸命运的能力。然而，Hox6 基因在 LMC 神经元中的具体作用和机制尚不清楚。我们表明，Hox6 基因对于 LMC 身份的各个方面都是至关重要的，并确定了它们在体内特异性所需的基序。尽管 Hox6 基因对于产生适当数量的 LMC 神经元是必要的，但它们对于诱导前肢 LMC 分子决定因素并不是绝对必要的。在没有 Hox6 活性的情况下，LMC 身份似乎通过一系列多样化的 Hox5-Hox8 基因家族来保留，这些基因家族足以将胸运动神经元重新编程为 LMC 命运。与早期 LMC 基因程序中似乎允许的 Hox 输入形成对比，个别 Hox 基因，如 Hoxc6，在促进 LMC 内运动神经元池多样性方面具有特定作用。对体内特异性所需基序的剖析表明，要么是交叉抑制相互作用，要么是与 Pbx 共因子的协同作用足以诱导 LMC 身份，其 N 端在转移到异源同源域时能够促进柱状，但不能促进池状身份。这些结果表明，Hox 蛋白通过许多旁系同源基因程序的收敛调节以及通过 N 端特异性决定因素编码的更受限制的作用来协调细胞命运特化的各个方面。
