Morphogen gradient reconstitution reveals Hedgehog pathway design principles

被引:85
作者
Li, Pulin [1 ]
Markson, Joseph S. [1 ]
Wang, Sheng [1 ]
Chen, Siheng [1 ]
Vachharajani, Vipul [1 ]
Elowitz, Michael B. [1 ,2 ,3 ]
机构
[1] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA
[2] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA
[3] CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA
基金
英国生物技术与生命科学研究理事会; 美国国家科学基金会;
关键词
SONIC HEDGEHOG; NEURAL-TUBE; RANGE; GENE; MECHANISMS; PATTERN; ROLES; FORM; SHH;
D O I
10.1126/science.aao0645
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In developing tissues, cells estimate their spatial position by sensing graded concentrations of diffusible signaling proteins called morphogens. Morphogen-sensing pathways exhibit diverse molecular architectures, whose roles in controlling patterning dynamics and precision have been unclear. In this work, combining cell-based in vitro gradient reconstitution, genetic rewiring, and mathematical modeling, we systematically analyzed the distinctive architectural features of the Sonic Hedgehog pathway. We found that the combination of double-negative regulatory logic and negative feedback through the PTCH receptor accelerates gradient formation and improves robustness to variation in the morphogen production rate compared with alternative designs. The ability to isolate morphogen patterning from concurrent developmental processes and to compare the patterning behaviors of alternative, rewired pathway architectures offers a powerful way to understand and engineer multicellular patterning.
引用
收藏
页码:543 / +
页数:6
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