Warrier Sunita, Nuwayhid Samer, Sabatino Julia A, Sugrue Kelsey F, Zohn Irene E
Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA; Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA.
Dev Biol. 2017 Jan 15;421(2):245-257. doi: 10.1016/j.ydbio.2016.11.009. Epub 2016 Nov 25.
Somitogenesis and subsequent axial skeletal development is regulated by the interaction of pathways that determine the periodicity of somite formation, rostrocaudal somite polarity and segment identity. Here we use a hypomorphic mutant mouse line to demonstrate that Supt20 (Suppressor of Ty20) is required for development of the axial skeleton. Supt20 hypomorphs display fusions of the ribs and vertebrae at lower thoracic levels along with anterior homeotic transformation of L1 to T14. These defects are preceded by reduction of the rostral somite and posterior shifts in Hox gene expression. While cycling of Notch target genes in the posterior presomitic mesoderm (PSM) appeared normal, expression of Lfng was reduced. In the anterior PSM, Mesp2 expression levels and cycling were unaffected; yet, expression of downstream targets such as Lfng, Ripply2, Mesp1 and Dll3 in the prospective rostral somite was reduced accompanied by expansion of caudal somite markers such as EphrinB2 and Hes7. Supt20 interacts with the Gcn5-containing SAGA histone acetylation complex. Gcn5 hypomorphic mutant embryos show similar defects in axial skeletal development preceded by posterior shift of Hoxc8 and Hoxc9 gene expression. We demonstrate that Gcn5 and Supt20 hypomorphs show similar defects in rostral-caudal somite patterning potentially suggesting shared mechanisms.
体节发生及随后的轴向骨骼发育受多种信号通路相互作用的调控,这些信号通路决定了体节形成的周期性、头-尾体节极性和节段身份。在此,我们使用一种低表达突变小鼠品系来证明,轴向骨骼发育需要Supt20(Ty20抑制因子)。Supt20低表达小鼠在胸段下部出现肋骨和椎骨融合,同时L1出现向T14的前部同源异型转化。这些缺陷之前,头侧体节减少,Hox基因表达向后移位。虽然Notch靶基因在后侧前体节中胚层(PSM)的循环似乎正常,但Lfng的表达减少。在前侧PSM中,Mesp2的表达水平和循环未受影响;然而,在前体节的预期头侧中,Lfng、Ripply2、Mesp1和Dll3等下游靶标的表达减少,同时尾侧体节标记物如EphrinB2和Hes7的表达增加。Supt20与含有Gcn5的SAGA组蛋白乙酰化复合体相互作用。Gcn5低表达突变胚胎在轴向骨骼发育中表现出类似的缺陷,之前Hoxc8和Hoxc9基因表达向后移位。我们证明,Gcn5和Supt20低表达小鼠在头-尾体节模式形成中表现出类似的缺陷,这可能暗示了共同的机制。