TY  - JOUR
AU  - Wittmann, Dominik M
AU  - Blöchl, Florian
AU  - Trümbach, Dietrich
AU  - Wurst, Wolfgang
AU  - Prakash, Nilima
AU  - Theis, Fabian J
TI  - Spatial analysis of expression patterns predicts genetic interactions at the mid-hindbrain boundary.
JO  - PLoS Computational Biology
VL  - 5
IS  - 11
SN  - 1553-7358
CY  - San Francisco, Calif.
PB  - Public Library of Science
M1  - DZNE-2020-02352
SP  - e1000569
PY  - 2009
AB  - The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level.
KW  - Algorithms
KW  - Animals
KW  - Brain: embryology
KW  - Brain: metabolism
KW  - Brain Mapping: methods
KW  - Computational Biology: methods
KW  - Diffusion
KW  - Fibroblast Growth Factor 8: genetics
KW  - Gene Expression Profiling: methods
KW  - Gene Expression Regulation, Developmental
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Models, Biological
KW  - Models, Statistical
KW  - Transcription, Genetic
KW  - Wnt1 Protein: genetics
KW  - Fgf8 protein, mouse (NLM Chemicals)
KW  - Wnt1 Protein (NLM Chemicals)
KW  - Wnt1 protein, mouse (NLM Chemicals)
KW  - Fibroblast Growth Factor 8 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:19936059
C2  - pmc:PMC2774268
DO  - DOI:10.1371/journal.pcbi.1000569
UR  - https://pub.dzne.de/record/136030
ER  -