Morphing heads

Bicoid protein is expressed at the anterior of the embryo. Image courtesy of Valérie Schaeffer, New York University, USA.

One classic theme in developmental biology is the idea of a morphogen. Morphogens have long been proposed to act autonomously, defining cell fates at different concentration levels, thereby generating positional information from a gradient (see Milestone 4). However, it wasn't until pioneering work by Fronhofer and Nüsslein-Volhard in 1986, and Driever and Nüsslein-Volhard in 1988, that the first classic morphogen in Drosophila melanogaster, Bicoid (Bcd), was identified.

Bcd is a maternal effect gene involved in anterior development in the fruitfly, and it controls the expression of zygotic segmentation genes, such as hunchback, in the developing embryo (see Milestone 13). Embryos from Bcd^−/− mothers develop without heads or other anterior structures, and Fronhofer and Nüsslein-Volhard demonstrated the clear rescue of this phenotype by transplanting wild-type anterior cytoplasm into mutant embryos. Results of this classic developmental biology experiment indicated that anterior cytoplasm was sufficient to induce anterior development and suppress posterior development wherever it was injected into the mutant embryos. The fact that Bcd mRNA could act over a long range to induce anterior development and suppress posterior development was later confirmed by Driever and Nüsslein-Volhard.

Using rabbit polyclonal antibodies to Bcd, Driever and Nüsslein-Volhard identified, in 1988, a 55 kDa protein that is localized in a visible gradient (with the highest concentration at the anterior) within the nuclei of cleaving embryos. This seminal paper was the first to identify a protein gradient in Drosophila embryos and led the authors to conclude that the protein was indeed a morphogen which had long-range effects on neighbouring cells. An accompanying manuscript from the same authors provided back-up genetic evidence, which demonstrated, correlatively, that Bcd was indeed a classic morphogen.

	I believe this was the first really solid molecular evidence for the much-discussed but controversial ideas about morphogen gradients.   Matthew Freeman

Subsequent work has indicated that Bcd, which was known to contain a homeodomain and control zygotic gene expression, binds directly to DNA. Using P-element germ-line transposition, Driever, Thoma and Nüsslein-Volhard showed how Bcd protein could generate a gradient — the target gene hunchback has both high- and low-affinity binding sites for Bcd, which ensure gene expression even at low levels of Bcd and hence generate a gradient. This small collection of manuscripts indicates what underlies a simple idea of a morphogen in vivo to ensure that a fly embryo knows its head from its tail.

Work on morphogens wasn't limited to Drosophila, and more recent and controverisal work in Xenopus has indicated that the TGF-β/activin-A family member XTC-MIF, also acts as a classic morphogen in mesoderm development, leading to instructive responses at different protein levels.

All of these papers demonstrate how classic ideas were confirmed by a combination of traditional developmental biology transplantation experiments, genetic manipulation and molecular biology, allowing us to appreciate the beauty of a simple idea in action. Even now, 15 years after their publication, these papers form a cornerstone of developmental biology teaching and bring theories on morphogens to life.