the role of spatially controlled cell proliferation in limb bud morphogenesis空间控制在肢芽细胞增殖的作用形态发生.pdfVIP

The Role of Spatially Controlled Cell Proliferation in Limb Bud Morphogenesis 1 1 1 1,2 1 Bernd Boehm , Henrik Westerberg , Gaja Lesnicar-Pucko , Sahdia Raja , Michael Rautschka , James 1,2 1 1,3 Cotterell , Jim Swoger , James Sharpe * 1 EMBL-CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), UPF, Barcelona, Spain, 2 MRC Human Genetics Unit, Edinburgh, Scotland, United Kingdom, 3 ICREA Professor, Centre for Genomic Regulation (CRG), UPF, Barcelona, Spain Abstract Although the vertebrate limb bud has been studied for decades as a model system for spatial pattern formation and cell specification, the cellular basis of its distally oriented elongation has been a relatively neglected topic by comparison. The conventional view is that a gradient of isotropic proliferation exists along the limb, with high proliferation rates at the distal tip and lower rates towards the body, and that this gradient is the driving force behind outgrowth. Here we test this hypothesis by combining quantitative empirical data sets with computer modelling to assess the potential role of spatially controlled proliferation rates in the process of directional limb bud outgrowth. In particular, we generate two new empirical data sets for the mouse hind limb—a numerical description of shape change and a quantitative 3D map of cell cycle times—and combine these with a new 3D finite element model of tissue growth. By developing a parameter optimization approach (which explores spatial patterns of tissue growth) our computer simulations reveal that the observed distrib