Sivakamasundari V, Kraus Petra, Sun Wenjie, Hu Xiaoming, Lim Siew Lan, Prabhakar Shyam, Lufkin Thomas
The Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
Department of Biology, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699, USA.
Biol Open. 2017 Feb 15;6(2):187-199. doi: 10.1242/bio.023218.
and play redundant, synergistic functions in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. They are conserved in mice and humans, whereby mutation/deficiency of human has been associated with kyphoscoliosis. By combining cell-type-specific transcriptome and ChIP-sequencing data, we identified the roles of / in cell proliferation, cartilage development and collagen fibrillogenesis, which are vital in early IVD morphogenesis. is up-regulated in the absence of , while is unaffected by the loss of We identified the targets compensated by a single- or double-copy of They positively regulate many of the cartilage genes known to be regulated by S and are connected to by a negative feedback loop. are intertwined with BMP and TGF-B pathways and we propose they initiate expression of chondrogenic genes during early IVD differentiation and subsequently become restricted to the outer annulus by the negative feedback mechanism. Our findings highlight how early IVD development is regulated spatio-temporally and have implications for understanding kyphoscoliosis.
并且在形成轴向骨骼的椎体和椎间盘（IVD）的硬骨细胞的模式形成和分化中发挥冗余的协同功能。它们在小鼠和人类中保守存在，其中人类[相关基因]的突变/缺陷与脊柱侧凸有关。通过结合细胞类型特异性转录组和ChIP测序数据，我们确定了[相关基因]在细胞增殖、软骨发育和胶原纤维形成中的作用，这些在早期IVD形态发生中至关重要。[相关基因]在[另一相关基因]缺失时上调，而[另一相关基因]不受[相关基因]缺失的影响。我们确定了由[相关基因]的单拷贝或双拷贝补偿的靶点。它们正向调节许多已知由S调节的软骨基因，并通过负反馈环与[相关基因]相连。[相关基因]与BMP和TGF - B信号通路相互交织，我们提出它们在早期IVD分化过程中启动软骨形成基因的表达，随后通过负反馈机制限制在外周纤维环。我们的发现突出了早期IVD发育如何在时空上受到调节，并对理解脊柱侧凸具有启示意义。
