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Morphogenesis (from the Greek morpheus 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.

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.

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? 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.


Embryogenesis is the process by which the embryo is formed and develops. It starts with the fertilization of the ovum, which is then called a zygote. The zygote undergoes rapid mitotic divisions with no significant growth (a process known as cleavage) and cellular differentiation, leading to development of an embryo. It occurs in both animal and plant development, but this article addresses the common features among different animals.

The zygote

The egg cell (and hence the fertilized egg) is always asymmetric, having an "animal pole" (future ectoderm and mesoderm) and a "vegetal pole" (future endoderm), it is also covered with different protective envelopes. The first envelope, the one which is in contact with the membrane of the egg, is made of glycoproteins and is called vitelline membrane (zona pellucida in mammals). Different taxa show different cellular and acellular envelopes.


The zygote undergoes rapid cell cycles with no significant growth, producing a cluster of cells that is the same size as the original zygote. Depending mostly on the amount of yolk in the egg, the cleavage can be holoblastic (total) or meroblastic (partial). The different cells derived from cleavage (up to the blastula stage) are called blastomeres.

In holoblastic eggs the first cleavage always occurs along the vegetal-animal axis of the egg, the second cleavage is perpendicular to the first. From here the spatial arrangement of blastomeres can follow various patterns, due to different planes of cleavage, in various organisms:

Cleavage patterns followed by holoblastic and meroblastic eggs

Holoblastic Meroblastic
Radial (sea urchin, amphioxus)Discoidal (fish, birds, reptiles)
Bilateral (tunicates, amphibians)Superficial (insects)
Spiral (annelids, mollusks)*
Rotational (mammals)*
Blastula and Gastrula

Blastulation begins after the cleavage has produced 128 cells, in this stage the embryo is called a blastula. The blastula is usually a spherical layer of cells (the blastoderm) surrounding a fluid-filled or yolk-filled cavity (the blastocoel).

In mammals blastulation leads to the formation of the blastocyst, which must not be confused with the blastula; even though they are similar in structure their cells have different fates.

During gastrulation cells migrate to the interior of the blastula, consequently forming two (in diploblastic animals) or three (triploblastic) germ layers. The embryo during this process is called a gastrula.

  • Among the different animals, different combinations of the following processes occur to place the cells in the interior of the embryo:
    • Epiboly (expansion of one cell sheet over other cells).
    • Ingression (cells move with pseudopods)
    • Invagination
    • Delamination (the external cells divide, leaving the daughter cells in the cavity)
    • Polar proliferation
  • Other major changes during gastrulation:
    • Heavy RNA transcription using 'zygotic' genes; up to this point the RNAs used were maternal (stored in the unfertilized egg).
    • Cells start major differentiation processes, losing their pluripotentiality.


At some point after the different germ layers are defined, organogenesis begins. The first stage in vertebrates is called neurulation, where the neural plate folds forming the neural tube. Other common organs or structures which arise at this time include the heart and somites, but from now on embryogenesis follows no common pattern among the different taxa of the animal kingdom.

In most animals organogenesis along with morphogenesis will result in a larva. The hatching of the larva, which must then undergo metamorphosis, marks the end of embryonic development.

Polymorphic variants

Recent immunohistochemical studies have shown that endometrial carcinomas are characterized by changes in glycosylation involving histo-blood group antigens. These carbohydrate determinants are present not only on erythrocytes but are also expressed by epithelial cells. Their expression herein has been shown to be related to the genetic status of the individual in terms of the ABO, Lewis and ABH-secretor type. Moreover, they show changes in expression relating to development, tissue-type, differentiation, cell-motility and malignancy. (1)

The expression pattern of A, B and H blood group antigens was evaluated by staining frozen sections with specific monoclonal antibodies developed by us and using the indirect immunoperoxidase method. The expression of blood group antigens was ubiquitously upregulated in the endothelial cells of fetal organs. In the process of their differentiation to endothelial naive embryonic mesenchymal cells expressed cytoplasmic ABH antigens. They were assumed as products of the activation of the respective genes. ABH antigen expression was considered as suggestive evidence for the assumption that blood group antigens could serve as early immunomorphologic markers of endothelial differentiation of mesenchymal cells, thus specifying the location of future blood vessels. Extending the conceptual framework of blood group antigens' significance we consider them as being possibly involved in the process of fetal morphogenesis. (2)

ABH expression undergoes developmental modulation in the human colorectal tract from positive to negative during embryogenesis, and is lost in adult cells. (3)

Histo-blood group antigens are found in most epithelial tissues. Meanwhile, several factors influence the type, the amount, and the histological distribution of histoblood group antigens, i.e. the ABO, Lewis, and saliva-secretor type of the individual, and the cell- and tissue type. Oligosaccharides with blood-group specificity are synthesized by the stepwise action of specific gene-encoded glycosyltransferases. In general, this stepwise synthesis of histo-blood group antigens correlates with cellular differentiation. The H and the Se genes both encode an al-2fucosyltransferase, which is responsible for the synthesis of blood group antigen H from precursor disaccharides. A new model for the participation of the Se/H-gene-encoded glycosyl transferases in synthesis of terminal histo-blood group antigens in human tissues is proposed; the type and degree of differentiation rather than the embryologic origin determines whether it is the H or the Se gene-encoded transferases that influence expression of terminal histo-blood group antigens in tissues. (4)

Enterocytic differentiated Caco-2 cells highly express H type 1 blood group antigen on the cell surface as well as activities of brush border membrane hydrolases, such as dipeptidyl peptidase IV and alkaline phosphatase. A strong correlation was observed between the amounts of H type 1 blood group antigen and the degrees of differentiation. Structural analysis with use of lectin affinity high performance liquid chromatography revealed that typical mucin-type sugar chains of the glycoproteins from undifferentiated cells have H type 2 group, linear polylactosamines, and core 1 structure. On the other hand, differentiated cells newly contain H type 1 and Le(b) groups and core 2 structure. Mucins with H type 1 group make contact with brush border membrane enzymes on differentiated cells. (5)

The parallel expression of ABH blood-group antigens and of the carcinoembryonic antigen was examined applying the biotin-streptavidin immunostaining system. Monoclonal antibodies to the ABH antigens newly produced by us and a polyclonal antibody to the carcinoembryonic antigen (Ortho) were used as primary antibodies. Human tumours derived from six different organs were studied. ABH antigens showed a heterogeneous expression. They were entirely missing in some neoplastic tissues and found in single or in clustered tumour cells in others. The staining for the carcinoembryonic antigen revealed stronger intensity and covered large malignant areas. The possible functions of ABH blood-group antigens as tumour-associated structures are discussed. A number of tumour-associated antigens have been identified which may serve to improve the early diagnostics of tumour processes in man. Recently, the blood-group antigens (BGA) from the ABO/H system have attracted the attention of many investigators who regard them as differentiation antigens and as tumour-associated structures. Oncogenesis is accompanied by a block in BGA biosynthesis as a result of an altered ontogenetical programme. This process leads to: a) deletion of BGA-structures in malignant cells; b) neoantigen expression (onco-developmental markers) and c) appearance of BGA-incompatible antigens. The aim of the present investigation is to examine the coexpression of A, B and H BGA and of the carcinoembryonic antigen (CEA) in malignant human tissues. Using the monoclonal antibodies (MAbs) to ABH-BGA newly produced in our laboratory, some insufficiently explored organs like the mammary gland and especially its metastases were also tested. (6)

Sequential appearance of ABH antigens in different animal species shows a progression from tissues of endodermal to ectodermal and finally mesodermal origin, human erythrocytes being the last cells to acquire these antigens. In view of this, ABH antigens should be called tissue or histo-blood group antigens rather than blood group antigens. In addition to the glycosyltransferases encoded by the ABO genes, several alpha-2, alpha-3 and alpha-4-fucosyltransferases are needed to account for the known ABH histo-blood group antigens. The genetic polymorphism of the genes encoding each of these enzymes defines inter-individual differences. In addition, in the same individual various tissues express these antigens in a different way. For each adult epithelial tissue, antigenic expression is related to cell maturation from germinal layer to surface epithelium. Differential expression is also found at various embryonal stages of the same cells. Examples of these phenomena are presented in an effort to gain further insight into the genetic regulation of the expression of these complex oligosaccharide molecules. (7

Cell surface antigen expression during proliferation and differentiation of human erythroid progenitors was examined using a combination of sequential micromanipulations of paired daughter cells derived from erythroid burst-forming units (BFU-E) and immuno-staining with a panel of monoclonal antibodies. Neither CD34 nor CD33 antigens were identified on the cells. CD36 and blood group A antigens were first identified on cells from aggregates containing 32 to 64 cells after 4 days of secondary culture and preceded the expression of glycophorin A and hemoglobin alpha. These results indicate that various cell surface antigens were sequentially expressed during the proliferation and differentiation of erythroid progenitors, and that our procedure may be useful for clarifying the morphologic and immunologic properties of hematopoietic stem cells. (8)



1. Skovlund VR. ABH and related histo-blood group antigens in normal & malignant human endometrium in relation to genetic and hormonal factors.APMIS Suppl. 1997;69:1-33.

2. Sarafian V, Dimova P, Georgiev I, Taskov H.ABH blood group antigen significance as markers of endothelial differentiation of mesenchymal cells. Folia Med (Plovdiv). 1997;39(2):5-9.

3. Cordon-Cardo C, Lloyd KO, Sakamoto J, McGroarty ME, Old LJ, Melamed MR. Immunohistologic expression of blood-group antigens in normal human gastrointestinal tract and colonic carcinoma. Int J Cancer. 1986 May 15;37(5):667-76.

4. Ravn V, Dabelsteen E. Tissue distribution of histo-blood group antigens.APMIS. 2000 Jan;108(1):1-28.

5. Amano J, Oshima M. Expression of the H type 1 blood group antigen during enterocytic differentiation of Caco-2 cells.J Biol Chem. 1999 Jul 23;274(30):21209-16.

6. Sarafian V, Popov A, Taskov H. Expression of A, B and H blood-group antigens and carcinoembryonic antigen in human tumours.Zentralbl Pathol. 1993 Nov;139(4-5):351-4.

7. Oriol R, Mollicone R, Coullin P, Dalix AM, Candelier JJ. Genetic regulation of the expression of ABH and Lewis antigens in tissues.APMIS Suppl. 1992;27:28-38.

8. Okumura N, Tsuji K, Nakahata T. Blood. 1992 Aug 1;80(3):642-50.