A morphogen is a substance whose non-uniform distribution governs the
pattern of tissue development in the process of
morphogenesis or
pattern formation
The science of pattern formation deals with the visible, ( statistically) orderly outcomes of self-organization and the common principles behind similar patterns in nature.
In developmental biology, pattern formation refers to the generation of ...
, one of the core processes of
developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.
Typically, morphogens are produced by source cells and diffuse through surrounding tissues in an embryo during early development, such that concentration gradients are set up. These gradients drive the process of differentiation of unspecialised
stem cells into different cell types, ultimately forming all the tissues and organs of the body. The control of morphogenesis is a central element in
evolutionary developmental biology (evo-devo).
History
The term was coined by
Alan Turing in the paper "
The Chemical Basis of Morphogenesis
"The Chemical Basis of Morphogenesis" is an article that the English mathematician Alan Turing wrote in 1952. It describes how patterns in nature, such as stripes and spirals, can arise naturally from a homogeneous, uniform state. The theory, w ...
", where he predicted a chemical mechanism for biological
pattern formation
The science of pattern formation deals with the visible, ( statistically) orderly outcomes of self-organization and the common principles behind similar patterns in nature.
In developmental biology, pattern formation refers to the generation of ...
, decades before the formation of such patterns was demonstrated.
The concept of the morphogen has a long history in developmental biology, dating back to the work of the pioneering ''
Drosophila'' (fruit fly)
geneticist,
Thomas Hunt Morgan, in the early 20th century.
Lewis Wolpert refined the morphogen concept in the 1960s with the
French flag model, which described how a 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 Nüsslein-Volhard was the first to identify a morphogen,
Bicoid, one of the
transcription factors present in a gradient in the ''Drosophila''
syncitial embryo. She was awarded the 1995
Nobel Prize in Physiology and Medicine for her work explaining the morphogenic
embryology
Embryology (from Greek ἔμβρυον, ''embryon'', "the unborn, embryo"; and -λογία, '' -logia'') is the branch of animal biology that studies the prenatal development of gametes (sex cells), fertilization, and development of embr ...
of the common fruit fly.
Groups led by Gary Struhl and Stephen Cohen then demonstrated that a secreted signalling protein,
decapentaplegic
Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly '' Drosophila melanogaster'' and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early ...
(the ''Drosophila'' homologue of
transforming growth factor beta), acted as a morphogen during the later stages of ''Drosophila'' development.
Mechanism
During early development, morphogen gradients result in the differentiation of specific
cell type
A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
s in a distinct spatial order. The morphogen provides spatial information by forming a
concentration gradient
Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) ...
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
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s. 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 combination 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 model is assumed to be a general mechanism by which cell type diversity can be generated in
embryonic development in animals.
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.
Genes and signals
A morphogen spreads from a localized source and forms a concentration gradient across a developing tissue. In developmental biology, 'morphogen' is rigorously used to mean a signalling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses that depend on morphogen concentration. This definition concerns the mechanism, not any specific chemical formula, so simple compounds such as
retinoic acid (the active metabolite of
retinol
Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...
or
vitamin A) may also act as morphogens. The model is not universally accepted due to specific issues with setting up a gradient in the tissue outlined in the
French flag model and subsequent work showing that the morphogen gradient of the Drosophila embryo is more complex than the simple gradient model would indicate.
Examples
Proposed mammalian morphogens include
retinoic acid, sonic hedgehog (
SHH), transforming growth factor beta (
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other s ...
)/bone morphogenic protein (
BMP), and
Wnt/
beta-catenin.
Morphogens in ''
Drosophila'' include
decapentaplegic
Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly '' Drosophila melanogaster'' and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early ...
and
hedgehog.
During development,
retinoic acid, a metabolite of
vitamin A, is used to stimulate the growth of the
posterior end of the organism.
Retinoic acid binds to
retinoic acid receptors that acts as transcription factors to regulate the expression of
Hox genes. Exposure of embryos to exogenous retinoids especially in the first trimester results in birth defects.
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other s ...
family members are involved in
dorsoventral patterning and the formation of some organs. Binding to TGF-β to type II
TGF beta receptors recruits type I receptors causing the latter to be transphosphorylated. The type I receptors activate
Smad proteins that in turn act as transcription factors that regulate gene transcription.
Sonic hedgehog (SHH) are morphogens that are essential to early patterning in the developing embryo. SHH binds to the
Patched receptor which in the absence of SHH inhibits the
Smoothened receptor. Activated smoothened in turn causes
Gli1,
Gli2, and
Gli3 to be translocated into the nucleus where they activate target genes such at
PTCH1 and
Engrailed.
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
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
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.
The general mechanism by which the morphogen model works, can explain the subdivision of tissues into patterns of distinct cell types, assuming it is possible to create and maintain a gradient. However, the morphogen model is often invoked for 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) which cannot be explained by model.
Eponyms
The organizing role that morphogens play during animal development was acknowledged in the 2014 naming of a new beetle genus, ''Morphogenia''. The type species, ''
Morphogenia struhli'', was named in honour of Gary Struhl, the US developmental biologist who was instrumental in demonstrating that the ''decapentaplegic'' and ''wingless'' genes encode proteins that function as morphogens during ''Drosophila'' development.
References
Further reading
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Morphogens