Embryogenese
 
Overview

1 Leerdoelen
2 Overview
3 Gametogenesis
4 Fertilization
5 Preimplantation
6 Implantation
7 Embryonale schijf
8 Embryonic phase
9 Fetal phase
10 Fetal membranes and placenta
11 Chromosomal and gene aberrations

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Presentation of the learning aims of the individual modules of this course or, in other words, the knowledge that the student should acquire while working through this course material.





Introduction to the course using the individual module summaries.





Gametes and their predecessor cells (the primordial germ cells) are differentiated from other somatic cells very early, and emigrate from the ectoderm (third week) via the extraembryonic endoderm (fifth week) into the primordium of the future gonads, the gonadal ridge. There, through an interaction with the coelomic epithelial cells, the primordium for the testis evolves in the seventh week, if a Y chromosome is present, or the primordium for the ovary in the eighth week, if it is absent .

The development of the testis occurs under the influence of testosterone among other factors. This is produced by the Leydig's interstitial cells that stem from the mesenchyma of the gonadal ridge, in an initial stage of activity (beginning of the 7th week). A second surge of secretory activity of the same cells starts at puberty. This leads to the maturation of the gonadal epithelium and to the growth and lumen formation in the tubuli seminiferi contorti. Spermatogenesis, which takes place from puberty onwards leads to a 64 day-long cycle in which the spermatogonia develop into sperm cells. At the beginning of spermatogenesis three steps of mitosis up to primary spermatocytes type I occur before meiosis commences. The first meiosis lasts 24 days, of which the prophase, with its four typical histological phases, takes the longest time. The secondary spermatocytes are engendered in the first meiosis and they immediately continue with the second meiosis, which is very brief because neither a synthesis of DNA nor a new grouping of the chromosomes takes place. The results of the second meiosis are the haploid spermatids. Within 24 days they differentiate themselves to become sperm cells that are then released into the lumen of the tubuli. Sperm cell production happens within innumerable temporally and spatially separated spermatogenesis waves that are spread throughout the whole lengths of the tubuli, that are wound up in each other in a spiral fashion. The sperm cell production is subject to large variations with an average value of around 100 million / day.

Oogenesis begins in roughly the 7th week (stage 20). The secondary germinal cords that have grown into the ovarian cortex decompose into individual groups of cells. A lively proliferation result, whereby the oogonia, similar to the spermatogonia, remain connected with each other via cellular bridges, permitting a synchronization of the mitosis and the subsequent meiosis steps (prophase). As soon as these oogonia have commenced with meiosis, they are named primary oocytes (12th week). All oocytes are arrested in the first meiosis at the end of the prophase. This interphase is termed dictyotene and can last until adulthood. The primary oocytes loose themselves from their cellular binding; they become surrounded by flat, somatic cells (follicle or granulosa cells) and are now called primordial follicles. In the 20th week nearly 7 million germ cells are formed and the whole cortex consists of these primordial follicles. After birth, only around 2 million are present and after puberty only around 250,000 remain in each ovary.






For a successful fertilization a mature spermatozoon, with a haploid set of chromosomes, and a mature oocyte, in which the second meiosis is arrested in the metaphase, are required. The union of the two gametes normally occurs in the ampullar part of the fallopian tube. The process in which he spermatozoon penetrates the oocyte is often designated as impregnation. This causes the oocyte to complete its second meiosis and also leads to the formation of a haploid set of chromosomes. The whole fertilization, up to the formation of the zygote (condition in which the united sets of chromosomes of the two pronuclei are in the metaphase of the first mitotic division) lasts roughly 24 hours. The goal is the replication of the diploid set of chromosomes and the determination of the chromosomal gender.

The mature spermatozoon consists of:

  • a head with the acrosome cap and the nucleus
  • the neck with two centriols,
  • the mid piece with mitochondria,
  • the principal piece,
  • and the end piece.

The sperm cells go through a series of activation procedures during their ascent through the cervix, uterine cavity and tube, which is known as capacitation. Thereby certain macromolecules, which originate in the seminal fluid, are eliminated from the surface of the sperm cells. Further, the sperm cells are made more mobile and prepared for the acrosome reaction.

After a successful impregnation of the oocyte by a spermatozoon a cortical reaction of the oocyte is triggered, which leads to a polyspermy block. Further, the completion of the second meiosis (meiosis II) thereby is effected. This procedure leads to the expulsion of the second polar body. The haploid nucleic material of the spermatozoon and of the oocyte swells and forms the paternal and maternal pronuclei. They approach each other slowly and roughly 22 hours after impregnation the zygote arises in that the two sets of chromosomes move to a equatorial position within the spindle. The first cell division takes place with the mitotic spindle, which comes from the proximal centrosome of the spermatozoon. With the creation of two daughter cells the fertilization is complete. The preimplantation phase has thereby begun.





After a successful fertilization, which takes place in the ampullary part of the fallopian tube, the embryo migrates through the tube into the uterine cavity. This migration takes six days. Along the way, the zygote divides several times, initially without increasing its volume because it is still enveloped by the pellucid zone. Daughter cells are engendered and one speaks now of the blastomere stage. After around 16 cells (morula) the compaction occurs in which the outer cells, the trophoblasts, form a compact epithelial structure. They are bound to each other via tight junctions and microvilli are formed towards the outside. The inner cells are thus protected from the influences of the outer milieu and can differentiate in other ways. There, an embryoblast comes into being. At the same time a fluid-filled space, the blastocyst cavity, is formed. One speaks now of a blastocyst. Subsequently the blastocyst emerges (hatches) from the pellucid zone and now finds itself as a free blastocyst on the mucosa surface in the uterine cavity. Two layers of cells can now be distinguished in the embryoblast: the epiblast and the hypoblast. Thereafter the free blastocyst embeds itself with the pole where the embryoblast is located into the endometrium; this is termed adplantation. With enzymes of its thropholast the blastocyst dissolves the endometrium and slowly penetrates deeply into it. With this the implantation has begun.





This module described the implantation stages of the blastocyst into the endometrium. This process extends over a time span from the end of the first week of embryonic development - namely from the moment of the hatching of the blastocyst - to the formation of the primitive placental circulation system in the middle of the second development week.

The endometrium structure (6.1) is favorable for an implantation of the blastocyst. It undergoes structural alterations that are regulated by sexual hormones. This cycle can be divided into three phases: menstrual, follicular und luteinic. Each is characterized by its own histological appearance of the endometrium, especially the glandular epithelium.

The implantation stage (6.2) begins with the apposition of the blastocyst at the uterine mucosa that normally is only formed in a region of the uterine wall.
An implantation of the blastocyst outside this zone means an extra-uterine pregnancy with serious consequences for the person's health. The implantation stages of the blastocyst in the uterine endometrium can be seen as taking place in three phases: apposition, adhesion and the embedding in the endometrium. The apposition can only occur during a certain time period within the course of the cycle, the so-called "implantation window". The apposition is connected with the maturation of the endometrium. As soon as the adhesion on the endometrium is complete, the cells that lie on the periphery of the blastocyst - the trophoblast - differentiate into two cell types: the syncytiotrophoblast (ST, on the outside) and the cytotrophoblast (CT, on the inside). Through their lytic activity the ST cells erode numerous structures of the endometrium and induce the decidual reaction. This process leads to the embedding of the blastocyst into the endometrium, whereby at this time it is completely surrounded by ST cells. During the second week extra-cytoplasmatic vacuoles appear in the ST. They combine into lacunae that later become filled with maternal blood, which comes from vessels eroded by the lytic ST activity. The primitive utero-placental circulatory system is thereby engendered.

The stages of the implantation result in a cascade of molecular mechanisms (6.3) that cause interactions between the trophoblast cells, on the one hand, and the cells and the extra-cellular matrix of the uterine mucosa, on the other. These interactions begin already at the moment the blastocyst hatches (preimplantation signals), changing the structural and functional properties of the uterus. These also promote the movement of the blastocyst in the direction of the implantation location and its modification in order to make the implantation easier. The interactions between the blastocyst and the uterine epithelium make sure the embryo has the right orientation as well as its adhesion to the uterine wall. The interactions between the blastocyst and the endometrium regulate the invasion of the trophoblast and the embedding of the blastocyst into the endometrium.

Several factors can lead to an abnormal implantation (6.4). In addition to the normal implantation zone there are a variety of locations, both within and outside the uterus, where the blastocyst can embed itself. Inside the uterus an implantation in the lower part leads to a placenta praevia. It forms in the cervix uteri and prevents a normal birth. Its detachment can also lead to serious clinical complications (hemorrhages).

With contraceptive methods one distinguishes between mechanical and chemical ones. Mechanical methods (spiral IUD's) have a double function: on the one hand, they work towards preventing an embedding of the blastocyst in the endometrium, and, on the other, they immobilize the sperm cells. With chemical methods, which are meant to hinder implantation or early embryonic development, either high hormone dosages ("morning after pill") or receptor antagonists (RU 486) are prescribed.





Deze module beschrijft de differentiatiestadia van de embryonale schijf van de 2de tot de 4de week van de ontwikkeling.

In de loop van de 2de week (7.1) differentieert het embryoblast zich in twee kiemlagen: het epiblast, waaruit het weefsel van het embryo en amnionepitheel ontstaat, en het hypoblast, dat de vesicula umbilicalis vormt.

Tijdens de 3de week van de ontwikkeling, ondergaat het epiblast een aantal complexe veranderingen die leiden tot de differentiatie van de drie embryonale kiemlagen. Het begint allemaal met het verschijnen van de primitieve streep (7.2), die een accumulatie is van cellen langsheen de middellijn. Deze streep is de locatie waarin lateraal emigrerende cellen verzinken om de diepe lagen te vormen van het mesoblast en het endoblast.
Zo ontstaat de vorming van de trilaminaire kiemschijf.
Het mesoblast is onderverdeeld in drie delen: paraxiaal, intermediair en laterale plaat mesoderm (7.2).
Het paraxiale gedeelte omgeeft de neurale buis en vormt later de somieten, waarin het wordt gesegmenteerd. Uit het intermediaire mesoderm ontstaat het urogenitaal systeem. Het laterale plaat mesoderm wordt onderverdeeld in het somatopleuraal en splanchnopleuraal mesoderm. Samen omsluiten ze het intra-embryonale coëloom (7.2).
Op dit ogenblik induceert de cilindervormige, mediale structuur, de notochorda, de differentiatie van het neuroblast. Dit proces wordt neurulatie genoemd (7.2). Het middelste gedeelte van het epiblast wordt dikker en vormt een gleuf en vervolgens een buis (neurale buis), waaruit het centrale zenuwstelsel wordt gevormd (7.2).
Van de randen van de neurale gleuf worden de cellen van de neurale lijst vrijgelaten, waaruit het grootste deel van het perifere zenuwstelsel wordt gevormd.

Twee overgangsstructuren, de notochorda en de primitieve streep, kunnen leiden tot ontwikkelingsanomalieën als ze niet volledig worden geresorbeerd (7.3).
Het sacro-coccygeaal teratoom vormt zichzelf uit restanten van de primitieve streep, het chordoma uit die van de notochorda. Caudale dysplasie omvat een groep syndromen die de onderste ledematen en het darmkanaal beïnvloeden. Een onvolledige sluiting van de craniale plooien van de neurale buis leidt tot een anencefalie. Als hetzelfde fenomeen zich voordoet in het caudale gedeelte van de neurale buis, ontstaan er diverse vormen van spina bifida.





The embryonic period comprises the first 8 weeks of pregnancy. It is divided into a preembryonic phase (from the 1rst to the 3rd week), in which the three germinal layers arise, and into the embryonic phase proper (from the 4th to 8th week), in which the embryonic organ anlagen arise.
The development takes place thanks to the genetic program and environmental factors that are tuned to each other precisely.

During the embryonic period the risk of congenital abnormalities is the greatest. Before, spontaneous miscarriages mostly occur. Later, the frequency of abnormalities and their effects are smaller. The most important teratogenic factors are infectious diseases, chemical substances, medications, and ionizing radiation.





The fetal period comprises roughly the two last trimesters of the pregnancy. This means 30 weeks in which the fetus enlarges the organ system that was laid down in the embryonic phase.
In this time, the expectant mother is monitored so that irregularities in the pregnancy can be caught as soon as possible. Today there exist for this purpose a variety of non-invasive and invasive prenatal diagnostic possibilities that can be employed, depending on the question being investigated.
The fetus and, in a much larger measure, the embryo is very sensitive to teratogenic substances. They can cause deformities to the organ systems in their formative stages. The possibility of prenatal diagnostics naturally evokes the question of pregnancy interruption when a severe genetically inherited problem has been diagnosed.




This module describes the structure and the differentiation of the tissues that the fetal membranes and placenta form, from the moment of implantation of the blastocyst into the uterine wall up to the end of the intrauterine development.

The development (10.1) of the extra-embryonic membranes begin at the moment of the differentiation of the blastocyst cells into an embryoblast and a trophoblast. The embryoblast forms the later embryo and the trophoblast the components of the embryonic appendage organs.

The forming of the placenta (10.2) is induced by the syncythiothrophoblast of the blastocyst, which triggers the decidual reaction of the uterine wall. This change of the endometrium depends on the stimulation by the hormones released by the ovary and placenta. The differentiation of the placenta begins with the formation of lacunae in the syncythiothrophoblast that are filled with maternal blood, which stems from the spiral arteries. The feto-placental circulation begins in the 3rd week, when the fetal vessels connect the placenta with the tissues of the embryonic body. Over the course of the pregnancy, the placenta adapts itself to the needs of the growing embryo (development of the placental villi).
In humans, the placenta is hemo-chorial, discoid, pseudo-cotyledonic, decidual and chorio-allantoid.

The placental circulation system (10.3) consists of a fetal and a maternal one, separated from one another by the placental barrier. The barrier controls the metabolic exchange processes between the embryo and mother (10.4). In addition, in the course of a normal pregnancy, the placenta fulfills other important physiologic tasks (e.g., endocrine).

In multiple pregnancies, the development of the fetal membrane is subject to certain changes (one distinguishes between dizygotic and monozygotic twins) (10.5.).

The umbilical cord (10.6) develops from the body stalk. With the development of the amniotic cavity the umbilical cord becomes enveloped by the amniotic epithelium and towards the end of the pregnancy, contains only two umbilical arteries and one umbilical vein. These structures are surrounded by connective tissue that stems from the extra-embryonic mesoblast. The embryonic umbilical cord, which swims in the amniotic cavity, lengthens with the progressive development of the embryo. The cavity is filled with amniotic fluid (10.8) which looks after various mechanical and metabolic functions between the mother and fetus. Bands in the amniotic fluid can lead to fetal abnormalities.

Of the various pathologies, which can influence placental development, we cite (10.9): complications of fetal (fetal erythroblastosis, chorion carcinoma, hydatid mole) or maternal (toxemia of pregnancy, eclampsia) origin.
In addition, there exist anomalies that are connected with an abnormal implantation location (ectopic pregnancy) as well as with the development of the placenta (placenta praevia). The insertion location of the umbilical cord at the placenta can also vary (marginal or eccentric insertion). All these anomalies lead either to an abnormal development of the fetus, complications at delivery, or to a miscarriage.




Pathogenic mutations are involved in alterations of the genetic material that causes illnesses. Basically, "too much" or "to little" genetic information leads to disorders. In other words, if the genetic material is not balanced, disease ensues. Most mutations lead to altered gene products. As consequences these can be disturbances in individual metabolic tasks but also alterations of the entire phenotype.

One distinguishes between two kinds of mutations:

  • Gene mutations
  • Chromosomal mutations

In gene mutations disruptions occur within a single gene. If whole portions of chromosomes are disrupted, one speaks of structural anomalies within a chromosome or, if the number of chromosomes has changed, of trisomies, monosomies, or, more generally of aneuploidies or numerical chromosomal aberrations.

It is important to state that most chromosome deviations arise randomly during gamete formation through non-disjunctions or chromosome breaks. Either such disorders (deletions, duplications, isochromies of individual chromosomes = disorders of the chromosome structure; trisomies, monosomies = disorders of the number of chromosomes) have immediate clinical consequences or they remain undiscovered in this generation because the genetic material, despite rearrangements, is still present in its entirety, i.e., is balanced. Nevertheless, balanced chromosomal aberrations lead to defective gamete formations. Through this, the disorder may appear phenotypically only in the next generation or the one after that. For example, fusions of acrocentric chromosomes 14/21 (= robertsonian translocations) can lead to a hereditary trisomy 21 or Down syndrome.

A smaller part of chromosomal deviations takes place after the fertilization in a cell line. This leads to mosaic forms.
With abnormalities and diseases one has again and again seen that a genetic disposition is indeed present (accumulation of diseases in families). Either several genes must be present, however, for the expression of the symptom (disease or abnormality) (=> polygeny) or still other influences must play a role that a disease breaks out or an abnormality appears (=> multifactorial inheritance). In addition, in certain mutations, genetic imprinting has a large influence on the phenotypes.

In the clinic, children with a deviating number or structure of their chromosomes have mostly multiple abnormalities, often combined with mental retardation. If smaller gene regions are affected, the disorders, depending on their severity, can appear only later. The following clinical criteria indicate possible chromosomal aberrations:

  • Pre- and postnatal growth disorders
  • Mental retardation
  • Abnormalities
  • Dysmorphic signs.

If there are indications in the anamnesis for an increased appearance of congenital abnormalities, monogenetic hereditary diseases or habitual miscarriages, genetic counseling should definitively be made available.