Nemec Stephen, Luxey Maëva, Jain Deepak, Huang Sung Aurélie, Pastinen Tomi, Drouin Jacques
Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada.
Department of Experimental Medicine, McGill University, Montreal, QC, H4A 3J1 Canada.
Development. 2017 Sep 15;144(18):3325-3335. doi: 10.1242/dev.154864. Epub 2017 Aug 14.
Forelimbs (FLs) and hindlimbs (HLs) develop complex musculoskeletal structures that rely on the deployment of a conserved developmental program. , a transcription factor gene with expression restricted to HL and absent from FL, plays an important role in generating HL features. The genomic mechanisms by which effects HL identity remain poorly understood. Here, we use expression profiling and analysis of direct Pitx1 targets to characterize the HL- and FL-restricted genetic programs in mouse and situate the -dependent gene network within the context of limb-specific gene regulation. We show that is a crucial component of a narrow network of HL-restricted regulators, acting on a developmental program that is shared between FL and HL. Pitx1 targets sites that are in a similar chromatin state in FL and HL and controls expression of patterning genes as well as the chondrogenic program, consistent with impaired chondrogenesis in HL. These findings support a model in which multifactorial actions of a limited number of HL regulators redirect the generic limb development program in order to generate the unique structural features of the limb.
前肢（FLs）和后肢（HLs）发育出复杂的肌肉骨骼结构，这依赖于一个保守的发育程序的展开。Pitx1是一种转录因子基因，其表达仅限于后肢，在前肢中不存在，在生成后肢特征方面发挥着重要作用。Pitx1影响后肢特征的基因组机制仍知之甚少。在这里，我们使用表达谱分析和对Pitx1直接靶标的分析来表征小鼠中后肢和前肢特异性的遗传程序，并将Pitx1依赖的基因网络置于肢体特异性基因调控的背景下。我们表明，Pitx1是后肢特异性调控因子的一个狭窄网络的关键组成部分，作用于前肢和后肢共有的发育程序。Pitx1靶向在前肢和后肢中处于相似染色质状态的位点，并控制模式基因的表达以及软骨生成程序，这与Pitx1缺陷型后肢中的软骨生成受损一致。这些发现支持了一个模型，即有限数量的后肢调控因子的多因素作用会重定向通用的肢体发育程序，以产生肢体独特的结构特征。
