Department of Physiology and Neuroscience, Smilow Neuroscience Program, Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
Genes Dev. 2012 Oct 1;26(19):2236-50. doi: 10.1101/gad.199133.112.
Polycomb repressive complexes (PRCs) establish and maintain gene repression through chromatin modifications, but their specific roles in cell fate determination events are poorly understood. Here we show an essential role for the PRC1 component Bmi1 in motor neuron (MN) subtype differentiation through dose-dependent effects on Hox gene expression. While Bmi1 is dispensable for generating MNs as a class, it has an essential role in specifying and determining the position of Hox-dependent MN columnar and pool subtypes. These actions are mediated through limiting anterior Hox expression boundaries, functions deployed in post-mitotic MNs, temporally downstream from morphogen gradients. Within the HoxC gene cluster, we found a progressive depletion of PRC-associated marks from rostral to caudal levels of the spinal cord, corresponding to major demarcations of MN subtypes. Selective ablation of Bmi1 elicits a derepression of more posterior Hox genes, leading to a switch in MN fates. Unexpectedly, Hox patterns and MN fates appear to be sensitive to absolute PRC1 activity levels; while reducing Bmi1 switches forelimb lateral motor column (LMC) MNs to a thoracic preganglionic (PGC) identity, elevating Bmi1 expression at thoracic levels converts PGC to LMC MNs. These results suggest that graded PRC1 activities are essential in determining MN topographic organization.
多梳抑制复合物（PRC）通过染色质修饰来建立和维持基因抑制，但它们在细胞命运决定事件中的具体作用知之甚少。在这里，我们通过对 Hox 基因表达的剂量依赖性影响，显示了 PRC1 成分 Bmi1 在运动神经元（MN）亚型分化中的重要作用。虽然 Bmi1 对于作为一类 MN 的产生是可有可无的，但它在指定和确定 Hox 依赖性 MN 柱状和池状亚型的位置方面具有重要作用。这些作用是通过限制前 Hox 表达边界来介导的，这些作用在有丝分裂后 MN 中发挥作用，时间上晚于形态发生梯度。在 HoxC 基因簇中，我们发现 PRC 相关标记物从脊髓的头侧到尾侧水平逐渐减少，这与 MN 亚型的主要划分相对应。Bmi1 的选择性缺失会引发更靠后的 Hox 基因的去抑制，导致 MN 命运的转变。出乎意料的是，Hox 模式和 MN 命运似乎对 PRC1 活性水平的绝对值敏感；虽然降低 Bmi1 将前肢外侧运动神经元（LMC）MN 转变为胸节前交感神经节（PGC）身份，但在胸段水平升高 Bmi1 表达会将 PGC 转化为 LMC MN。这些结果表明，PRC1 活性的梯度对于确定 MN 的拓扑组织是必不可少的。
