Morphogen

A morphogen is a substance governing the pattern of tissue development and, in particular, the positions of the various specialized cell types within a tissue. It spreads from a localized source and forms a concentration gradient across a developing tissue.

In developmental biology a morphogen is rigorously used to mean a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration.

Well-known morphogens include: Decapentaplegic / Transforming growth factor beta, Hedgehog / Sonic Hedgehog, Wingless / Wnt, Epidermal growth factor, and Fibroblast growth factor.

Morphogens are defined conceptually, not chemically, so simple chemicals such as retinoic acid may also act as morphogens.

Additional recommended knowledge

Essential Laboratory Skills Guide

How to quickly check pipettes?

Correct Test Weight Handling Guide: 12 Practical Tips

Introduction

During early development, morphogen gradients generate different cell types in distinct spatial order. The morphogen provides spatial information by forming a concentration gradient that subdivides a field of cells by inducing or maintaining the expression of different target genes at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold target genes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combinations of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This is a general mechanism by which cell type diversity can be generated in animal development.

Some of the earliest and best-studied morphogens are transcription factors that diffuse within early Drosophila melanogaster (fruit fly) embryos. However, most morphogens are secreted proteins that signal between cells.

Fruit fly

Drosophila melanogaster has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within a syncytium prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryos transcription factors such as Bicoid or Hunchback can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence that homeobox transcription factors similar to these can pass directly through cell membranes, this mechanism is not believed to contribute greatly to morphogenesis in cellularized systems.

In most developmental systems, such as human embryos or later Drosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembrane receptor proteins, which use an elaborate process of signal transduction to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitial Drosophila embryo.

Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers' to which transcription factors bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated.

Thus, the general mechanism by which morphogens subdivide tissues into patterns of distinct cell types is well understood. However, morphogens often have additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction). These activities of morphogens are much less understood and are the subject of current research efforts in the field of developmental biology.

Discovery

The morphogen idea has a long history in developmental biology, dating back to the work of the pioneering Drosophila geneticist, Thomas Hunt Morgan, in the early 20th century. However, it was Lewis Wolpert who refined the morphogen concept in the 1960s with his famous 'french flag' model which described how morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence. Christiane Nusslein-Volhard identified the first morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. Two labs, that of Gary Struhl and that of Stephen Cohen, then demonstrated that a secreted signalling protein, Decapentaplegic (the Drosophila homolgue of Transforming Growth Factor Beta), acted as a morphogen during later stages of Drosophila development.

Subsequent studies of the development of many different animals has confirmed the widespread importance of morphogens in governing animal development.

NCBI resources

From the National Center for Biotechnology Information:

• OMIM
• PubMed