Generation of animal form by the Chordin/Tolloid/BMP gradient: 100 years after D'Arcy Thompson

Abstract

The classic book "On Growth and Form" by naturalist D'Arcy Thompson was published 100 years ago. To celebrate this landmark, we present experiments in the Xenopus embryo that provide a framework for understanding how simple, quantitative transformations of a morphogen gradient might have affected evolution and morphological diversity of organisms. D'Arcy Thompson proposed that different morphologies might be generated by modifying physical parameters in an underlying system of Cartesian coordinates that pre-existed in Nature and arose during evolutionary history. Chordin is a BMP antagonist secreted by the Spemann organizer located on the dorsal side of the gastrula. Chordin generates a morphogen gradient as first proposed by mathematician Alan Turing. The rate-limiting step of this dorsal-ventral (D-V) morphogen is the degradation of Chordin by the Tolloid metalloproteinase in the ventral side. Chordin is expressed at gastrula on the dorsal side where BMP signaling is low, while at the opposite side peak levels of BMP signaling are reached. In fishes, amphibians, reptiles and birds, high BMP signaling in the ventral region induces transcription of a secreted inhibitor of Tolloid called Sizzled. By depleting Sizzled exclusively in the ventral half of the embryo we were able to expand the ventro-posterior region in an otherwise normal embryo. Conversely, ventral depletion of Tolloid, which stabilizes Chordin, decreased ventral and tail structures, phenocopying the tolloid zebrafish mutation. We explain how historical constraints recorded in the language of DNA become subject to the universal laws of physics when an ancestral reaction-diffusion morphogen gradient dictates form.

Transcriptome analysis of regeneration during Xenopus laevis experimental twinning

“…1). However, the strong decrease in levels of sizzled expression during twinning suggests that Chordin protein levels might be increased indirectly, though the competitive inhibition of the Tolloid enzymes that degrade Chordin (Lee et al, 2006;De Robertis et al, 2017).…”

“…The RNA-seq data from the 30 individual libraries bisected at midblastula and allowed to regenerate until gastrula stages 10.5 or 12 (available in supplemental tables S1 and S2 in a searchable Excel format, or as raw data at Gene Expression Omnibus database of the NIH, number GSE124563), provide a very rich resource to mine for genes regulated in the early vertebrate embryo. For example, all of the known Spemann organizer and ventral center genes (Reversade and De Robertis, 2005;De Robertis et al, 2017), as well as others previously unknown, are strongly represented in the dorsal and ventral half-embryos bisected at stage 8 and allowed sagittal half-embryos. They were all ventrally enriched transcripts, and found only in one embryo.…”

Embryonic regeneration by relocalization of the Spemann organizer during twinning in Xenopus

“…The findings reported here are embryological in nature, and do not address the molecular pathways by which the D-V gradient is respecified. The Spemann organizer requires low BMP signaling for its formation, while the opposite is true for the ventral center ( 11 , 26 ). It is conceivable that as BMP levels start rising in the ventral side, they displace the formation of the Spemann organizer.…”

“…In the reciprocal reaction, once the organizer is formed, it will secrete BMP and Wnt inhibitors that will dampen BMP signals. The Chd–BMP pathway is regulated by the metalloproteinase Tolloid and its inhibitor Sizzled ( 12 , 26 ), and it can be expected that these molecules might play a role as well.…”

On “Growth and Form” and ASAPbio reform (Editorial)

“…Scientific work and creation by Stephen Jay Gould, Conrad Waddington, John Maynard Smith, Alan Turing, Paul Jackson Pollock, Eduardo Paolozzi, and others may serve as examples. This seems to be especially true regarding the most striking Thompson's theory of transformed coordinates (Briscoe and Kicheva, 2017;Durston and Zhu, 2017;De Robertis, Moriyama, and Colozza, 2017). According to the theory, different biological forms can be explained through Cartesian coordinate transformations of another form.…”