Four-dimensional realistic modeling of pancreatic organogenesis

doi:10.1073/pnas.0808725105

Four-dimensional realistic modeling of pancreatic organogenesis

^aComputational Biology Group, Microsoft Research, Cambridge CB3 0FB, United Kingdom;
Departments of ^bComputer Science and Applied Mathematics and
^cImmunology, Weizmann Institute of Science, Rehovot 76100, Israel; and
^dDepartment of Cellular Biochemistry and Human Genetics, Hadassah Medical School, Hebrew University, Jerusalem 91905, Israel

Communicated by Leroy E. Hood, Institute for Systems Biology, Seattle, WA, October 14, 2008 (received for review November 9, 2007)

Abstract

Organogenesis, the process by which organs develop from individual precursor stem cells, requires that the precursor cells proliferate, differentiate, and aggregate to form a functioning structure. This process progresses through changes in 4 dimensions: time and 3 dimensions of space—4D. Experimental analysis of organogenesis, by its nature, cuts the 4D developmental process into static, 2D histological images or into molecular or cellular markers and interactions with little or no spatial dimensionality and minimal dynamics. Understanding organogenesis requires integration of the piecemeal experimental data into a running, realistic and interactive 4D simulation that allows experimentation and hypothesis testing in silico. Here, we describe a fully executable, interactive, visual model for 4D simulation of organogenic development using the mouse pancreas as a representative case. Execution of the model provided a dynamic description of pancreas development, culminating in a structure that remarkably recapitulated morphologic features seen in the embryonic pancreas. In silico mutations in key signaling molecules resulted in altered patterning of the developing pancreas that were in general agreement with in vivo data. The modeling approach described here thus typifies a useful platform for studying organogenesis as a phenomenon in 4 dimensions.

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Footnotes

¹To whom correspondence should be addressed. E-mail: dharel{at}weizmann.ac.il
Author contributions: Y.S. designed research; Y.S. performed research; I.R.C., Y.D., and D.H. analyzed data; and Y.S., I.R.C., and D.H. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0808725105/DCSupplemental.
↵* The current model focuses on the dorsal pancreatic development but can be extended to cover the similar process at the ventral tissue.
↵† Data in Figs. 1 and ,4 are reprinted from ref. ,11 by permission of Macmillan Publishers Ltd. Data in ,Figs. 2 and ,7 are reprinted from ref. ,9 by permission of Elsevier. Data in ,Fig. 4 (,21, ,22) are reproduced with permission of the Company of Biologists. Data in ,Fig. 3 are reprinted from ref. ,7 by permission of Wiley–Liss, Inc., a subsidiary of John Wiley & Sons, Inc.