Localized heterochrony integrates overgrowth potential of oncogenic clones.
Localized heterochrony integrates overgrowth potential of oncogenic clones.
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DOI：
10.1242/dmm.049793
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发表时间：
2023-02-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
体细胞突变经常发生，并可能在胚胎发生期间出现，导致突变克隆的拼凑形成。这种嵌合现象与广泛的发育异常有关；然而，其病因尚不清楚。携带PIK3CA或AKT1常见体细胞致癌突变的患者可出现不成比例的大手指或四肢。携带致癌突变的克隆常常导致不受控制的增殖，如何导致受控和协调的过度生长尚不清楚。我们使用斑马鱼来探索在发育过程中致癌克隆的生长动力学。在这里，在克隆的一个子集中，我们观察到鳍骨骼比例的局部增加，与患者的过度生长表型非常相似。我们揭示了这些过度生长的细胞和发育机制，并确定了克隆扩增的细胞类型和时间。协调过度生长与骨发育早期前软骨形成阶段的快速克隆扩张有关，诱导了驱动骨大小变化的异慢性转变。我们的研究详细说明了发育如何整合和转化致癌克隆的生长潜力，从而塑造体细胞突变的表型后果。摘要：携带AKT1或PIK3CA体细胞致癌突变的软骨前细胞过度增殖导致长骨形成和骨骼巨人症的异慢性转移。
Somatic mutations occur frequently and can arise during embryogenesis, resulting in the formation of a patchwork of mutant clones. Such mosaicism has been implicated in a broad range of developmental anomalies; however, their etiology is poorly understood. Patients carrying a common somatic oncogenic mutation in either PIK3CA or AKT1 can present with disproportionally large digits or limbs. How mutant clones, carrying an oncogenic mutation that often drives unchecked proliferation, can lead to controlled and coordinated overgrowth is unknown. We use zebrafish to explore the growth dynamics of oncogenic clones during development. Here, in a subset of clones, we observed a local increase in proportion of the fin skeleton closely resembling overgrowth phenotypes in patients. We unravel the cellular and developmental mechanisms of these overgrowths, and pinpoint the cell type and timing of clonal expansion. Coordinated overgrowth is associated with rapid clone expansion during early pre-chondrogenic phase of bone development, inducing a heterochronic shift that drives the change in bone size. Our study details how development integrates and translates growth potential of oncogenic clones, thereby shaping the phenotypic consequences of somatic mutations. Summary: Overproliferation of pre-chondrogenic cells carrying a somatic oncogenic mutation in AKT1 or PIK3CA cause a heterochronic shift in long bone formation and skeletal gigantism.
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影响因子：
1.5
作者：
DeLaurier, April;Eames, B. Frank;Blanco-Sanchez, Bernardo;Peng, Gang;He, Xinjun;Swartz, Mary E.;Ullmann, Bonnie;Westerfield, Monte;Kimmel, Charles B.
通讯作者：
Kimmel, Charles B.
影响因子：
20.1
作者：
Detter MR;Snellings DA;Marchuk DA
通讯作者：
Marchuk DA
影响因子：
2
作者：
Keppler-Noreuil, Kim M.;Sapp, Julie C.;Lindhurst, Marjorie J.;Parker, Victoria E. R.;Blumhorst, Cathy;Darling, Thomas;Tosi, Laura L.;Huson, Susan M.;Whitehouse, Richard W.;Jakkula, Eveliina;Grant, Ian;Balasubramanian, Meena;Chandler, Kate E.;Fraser, Jamie L.;Gucev, Zoran;Crow, Yanick J.;Brennan, Leslie Manace;Clark, Robin;Sellars, Elizabeth A.;Pena, Loren D. M.;Krishnamurty, Vidya;Shuen, Andrew;Braverman, Nancy;Cunningham, Michael L.;Sutton, V. Reid;Tasic, Velibor;Graham, John M., Jr.;Geer, Joseph, Jr.;Henderson, Alex;Semple, Robert K.;Biesecker, Leslie G.
通讯作者：
Biesecker, Leslie G.
影响因子：
4.5
作者：
Das A;Crump JG
通讯作者：
Crump JG
影响因子：
64.8
作者：
Li, Ruoyan;Di, Lin;Wu, Chen
通讯作者：
Wu, Chen