Morphogenesis

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For the band, see Morphogenesis (band).

Morphogenesis (from the Greek morphê shape and  genesis creation) is  one of three fundamental aspects of developmental biology along with the control of cell growth and  cellular differentiation. Morphogenesis is  concerned with the shapes of tissues, organs and  entire organisms and  the positions of the various specialized cell types. Cell growth and  differentiation can take place in cell culture or  inside of tumor cell masses without the normal morphogenesis that is  seen in an  intact organism. The study of morphogenesis involves an  attempt to understand the processes that control the organized spatial distribution of cells that arises during the embryonic development of an  organism and  which give rise to the characteristic forms of tissues, organs and  overall body anatomy. In the human embryo, the change from a cluster of nearly identical cells at the blastula stage to a post-gastrulation embryo with structured tissues and  organs is  controlled by the genetic "program" and  can be modified by environmental factors.

[edit] History

Some of the earliest ideas on how physical and  mathematical processes and  constraints affect biological growth were written by D'Arcy Wentworth Thompson and  Alan Turing. These works postulated the presence of chemical signals and  physico-chemical processes such as diffusion, activation and  deactivation in cellular and  organismic growth. The fuller understanding of the mechanisms involved in actual organisms required the discovery of DNA and  the development of molecular biology and  biochemistry.

[edit] Molecular basis

Several types of molecules are  particularly important during morphogenesis. Morphogens are  soluble molecules that can diffuse and  carry signals that control cell differentiation decisions in a concentration-dependent fashion. Morphogens typically act through binding to specific protein receptors. an  important class of molecules involved in morphogenesis are  transcription factor proteins that determine the fate of cells by interacting with DNA. These can be coded for by master regulatory genes and  either activate or  deactivate the transcription of other genes and, in turn, these secondary gene products can regulate the expression of still other genes in a regulatory cascade. Another class of molecules involved in morphogenesis are  molecules that control cell adhesion. For example, during gastrulation clumps of stem cells switch off their cell-to-cell adhesion, become migratory, and  take up new positions with an  embryo where they again  activate specific cell adhesion proteins and  form new tissues and  organs. Several examples that illustrate the roles of morphogens, transcription factors and  cell adhesion molecules in morphogenesis are  discussed below.

[edit] Cellular basis

Morphogenesis arises because of changes in the cellular structure. Certain cell types sort out. The ability of cells to do this comes from differiential changes in cellular structure. There are  two types of cells epithelial cells and  mesenchymal cells. By changing from one cell type to another, cells are  able to move around and  associate with other like cells.

[edit] Adhesion

Cells sort out in different layers due to the differential adhesion model or  thermodynamic model. This model states that cells sort based upon differences in adhesion between the cells. Cells that move to the center of a mixed aggregate of cells have  the strongest adhesion.

The molecules responsible for adhesion are  called cell adhesion molecules (CAMs). Several types of cell adhesion molecules are  known and  one major class of these molecules are  cadherins. Cadherins are  a calcium dependent transmembrane protein that connects to the actin cytoskeleton through binding to trimeric proteins made up of a, b, and  g catenins. Cadherins bind to other cadherins in a like-like manner (E-cadherins bind to other E-cadherins) or  homophilic interactions.

[edit] Extracellular Matrix

The extracellular matrix (ECM) is  involved with separating tissues, providing structural support or  providing a structure for cells to migrate on. Collagen, laminin, and  fibronectin are  the major molecules and  are secreted and  assembled into sheets, fibers and  gels. Multisubunit transmembrane receptors called integrins are  used to bind to the ECM. Integrins bind extracellularly to fibronectin, laminin or  other ECM components and  intracellularly to microfilament binding proteins a-actinin and  talin to link the cytoskeleton with the outside. Integrins also serve as receptors to trigger signal transduction cascades when binding to the ECM.

[edit] Anterior-posterior axis patterning in Drosophila

One of the best understood morphogenetic systems is  the patterning along the future head to tail (antero-posterior) axis of the fruit fly Drosophila melanogaster. The development of Drosophila is  particularly well studied, and  it is  representative of one major class of insects, called insecta. Other multicellular organisms sometimes use similar mechanisms for axis formation, although the relative importance of signal transfer between the earliest cells of many developing organisms is  greater than in the example described here.

[edit] Maternal effect genes

Figure 1. mRNA distributions.

Figure 2. Protein distributions.

The building-blocks of anterior-posterior axis patterning in Drosophila are  laid out during egg formation (oogenesis), well before the egg is  fertilized and  deposited. The developing egg (oocyte) is  polarized by differentially localized mRNA molecules.

The genes that code for these mRNAs, called maternal effect genes, encode for proteins that get translated upon fertilization to establish concentration gradients that span the egg. Bicoid and  hunchback are  the maternal effect genes that are  most important for patterning of anterior parts (head and  thorax) of the Drosophila embryo. Nanos and  Caudal are  maternal effect genes that are  important in the formation of more  posterior abdominal segments of the Drosophila embryo.

Cytoskeletal elements such as microtubules are  polarized within the oocyte and  can be used to allow the localization of mRNA molecules to specific parts of the cell. Maternally synthesized bicoid mRNAs attach to microtubules and  are concentrated at the anterior ends of forming Drosophila eggs. Nanos mRNAs also attach to the egg cytoskeleton but they concentrate at the posterior ends of the eggs. Hunchback and  caudal mRNAs lack special location control systems and  are fairly evenly spread throughout the interior of egg cells.

When the mRNAs from the maternal effect genes are  translated into proteins a Bicoid protein gradient forms at the anterior end of the egg. Nanos protein forms a gradient at the posterior end. The Bicoid protein blocks translation of caudal mRNA so Caudal protein is  made only in the posterior part the cell. Nanos protein binds to the hunchback mRNA and  blocks its translation in the posterior end of Drosophila embryos.

The Bicoid, Hunchback, and  Caudal proteins are  transcription factors. Bicoid has a DNA-binding homeodomain that binds both DNA and  the nanos mRNA. Bicoid binds a specific RNA sequence in the 3' untranslated region of caudal mRNA and  blocks translation.

Hunchback protein levels in the early embryo are  significantly augmented by new hunchback gene transcription and  translation of the resulting zygotically produced mRNA. During early Drosophila embryogenesis there are  nuclear divisions without cell division. The many nuclei that are  produced distribute themselves around the periphery of the cell cytoplasm. Gene expression in these nuclei is  regulated by the Bicoid, Hunchback, and  Caudal proteins. For example, Bicoid acts as a transcriptional activator of hunchback gene transcription.

Figure 3. bicoid gradient

Figure 4. nanos gradient

[edit] Gap genes

Figure 5. Gap genes.

The other important function of the gradients of Bicoid, Hunchback, and  Caudal proteins is  in the transcriptional regulation of other zygotically expressed proteins. Many of these are  the protein products derived from members of the "gap" family of developmental control genes. Hunchback, krüppel, giant, tailless and  knirps are  all gap genes. Their expression patterns in the early embryo are  determined by the maternal effect gene products and  shown in the diagrams on the right side of this page. The gap genes are  part of a larger family called the segmentation genes. These genes establish the segmented body plan of the embryo along the anterior-posterior axis. The segmentation genes specify 14 "parasegments" that are  closely related to the final anatomical segments. The gap genes are  the first layer of a hierarchical cascade of the segmentation control genes.

Proteins such as Bicoid can be described as morphogens that act within the syncytial blastoderm of the early Drosophila embryo. These intracellular morphogens enter the nuclei and  act as transcription factors to control expression of the gap genes.

In the blastoderm stage of Drosophila morphogenesis four types of nuclear specification can be distinguished:

• Anterior (head and  thorax)
• Posterior (abdomen)
• Dorso-ventral
• Terminal (special structures at the unsegmented ends of the embryo)

[edit] Additional segmentation genes

Figure 6. Pair rule.

Two additional classes of segmentation genes are  expressed after the gap gene products. The pair-rule genes are  expressed in striped patterns of seven bands perpendicular to the anterior-posterior axis (see Figure 6, even-skipped). These patterns of expression are  established within the syncytial blastoderm. After these initial patterning events, cell membranes form around the nuclei of the syncytial blastoderm converting it  to a cellular blastoderm.

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Figure 7. Reciprocal signaling between Wingless and  Hedgehog producing cells.

The expression patterns of the final class of segmentation genes, the segment polarity genes, are  then fine-tuned by interactions between the cells of adjacent parasegments (see the example, engrailed, Figure 7). The Engrailed protein is  a transcription factor (yellow in Figure 7) that is  expressed in one row of cells at the edge of each parasegment. This expression pattern is  initiated by the pair-rule genes (like even-skipped) that code for transcription factors that regulate the engrailed gene's transcription in the syncytial blastoderm.

Cells that make Engrailed can make the cell-to-cell signaling protein Hedgehog (green in Figure 7). Hedgehog is  not free to move very far and  activates a thin stripe of cells adjacent to the Engrailed-expressing cells. Only cells to one side of the Engrailed-expressing cells are  competent to respond to Hedgehog because they express the receptor protein Patched (blue in Figure 7). Cells with activated Patch receptor make the Wingless protein (red in Figure 7). Wingless protein acts the adjacent rows of cells by activated its cell surface receptor, Frizzled.

Wingless also acts on Engrailed-expressing cells to stabilize Engrailed expression after the cellular blastoderm forms. The reciprocal signaling by Hedgehog and  Wingless stabilizes the boundary between each segment. The Wingless protein is  called "wingless" because of the phenotype of some wingless mutants. Wingless also functioned during metamorphosis to coordinate wing formation.

The transcription factors that are  coded for by segmentation genes regulate yet another family of developmental control genes, the homeotic selector genes. These genes exist in two ordered groups on Drosophila chromosome 3. The order of the genes on the chromosome reflects the order that they are  expressed along the anterior-posterior axis of the developing embryo. The Antennapedia group of homeotic selector genes includes labial, antennapedia, sex combs reduced, deformed, and  proboscipedia. Labial and  Deformed proteins are  expressed in head segments where they activate the genes that define head features. Sex-combs-reduced and  Antennapedia specify the properties of thoracic segments. The bithorax group of homeotic selector genes control the specializations of the third thoracic segment and  the abdominal segments.

In 1995, the  or  Medicine">Nobel Prize for Physiology or  Medicine was awarded for studies concerning the genetic control of early embryonic development to Christiane Nüsslein-Volhard, Edward B. Lewis and  Eric Wieschaus. Their researches on genetic screening for embryo patterning mutants revealed the role played in early embryologic development by Homeobox genes like bicoid. an  example of a homeotic mutation is  the so-called antennapedia mutation. In Drosophila, antennae and  legs are  created by the same basic "program", they only differ in a single transcription factor. If this transcription factor is  damaged, the fly grows legs on its head instead of antennae. See images of this "antennapedia" mutant and  others, at FlyBase.

The term morphogenesis can also be used to describe the development of unicellular life forms that do not have  an embryonic stage in their life cycle, or  to refer to the evolution of a body structure within a taxonomic group. Morphogenetic responses may be induced in organisms by hormones, or  by environmental chemicals ranging from substances produced by other organisms to toxic chemicals or  radionuclides released as pollutants, and  other plants.

[edit] See also

• embryogenesis
• embryo
• model organism
• Drosophila embryogenesis
• Tagmosis
• Projective Geometry