Overview

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.

The first sign of cardiac development is the cardiogenic plate that is still to be found cranially outside the embryo. The development of the heart then goes rapidly through 3 main phases:

• plexiform phase
• tubular phase
• loop phase

The flexion of the embryo causes the tissue of the original cardiogenic plate, which is enveloped by the pericardial cavity, to move into a ventral position. It consists of epicardium, myocardim and endocardium. A gelatinous mass, the cardiac jelly, temporarily forms between the myo- and endocardium and this is of decisive importance for the subsequent tube formation.

On the inside, diverse differentiation processes also take place whereby the blood is pumped through the heart, initially serially, and later in parallel. The following restructuring processes occur:

• Shifting of the inflow tract to the right
• Shifting the atrio-ventricular plane into the middle
• Dividing the atria and ventricles by septa
• Dividing of the outflow tracts by septa

The vessels near the heart are influenced in their development by the right-left determination of the heart. Certain portions of the venous and arterial systems atrophy and others develop further for this reason.

At birth large pressure changes take place. On the one hand, the low pressure area of the placenta falls away while, on the other hand, the pressure in the pulmonary circulation system decreases due to the distention of the lungs following the beginning of breathing. These two events cause the pressure in the left part of the heart to increase and in the right part of the heart to sink. The foramen ovale between the right and left atria closes thereby and the ductus arteriosus obliterates at the same time. Now the pulmonary circulation system is completely separated from the systemic one and they now operate in series.

The cardiac pacemaker and signal conduction system is important for a coordinated sequence of cardiac contractions. The sinus node is already delimited relatively early. The AV node and the bundle of His follow afterwards.
Thanks to the sympathetic, parasympathetic and sensory innervation the heart can adequately deal with loads.

In cardiac pathologies cardiac vitia (defects) without shunts and those with shunts are distinguished. With the latter, there are right-left shunts that lead to a cyanosis as well as left-right shunts that are acyanotic. In addition, inlet abnormalities of the large vessels can be observed.

Hematopoiesis is the term for the formation of blood cells out of pluripotent stem cells that originate in the aorto-gonado-mesonephric region. From these arise on the one hand the lymphoid stem cells that differentiate during the fetal period in the primary lymphatic organs - thymus and bone marrow – into immunocompetent B and T cells. On the other hand, myeloid stem cells, out of which all the other blood cells arise, also differentiate.

Initially, erythropoiesis is mainly in the foreground because O2 diffusion is soon insufficient to nourish the embryo. An initial extraembryonic phase of erythropoiesis occurs in the umbilical vesicle. These erythrocytes contain nuclei.
Intraembryonically erythropoiesis continues in the hepato-lienal phase, whereby these erythrocytes no longer have nuclei. In the second half of the pregnancy erythropoiesis occurs almost only in the bone marrow (myeloid phase). The composition of the embryo-fetal hemoglobin of the erythrocytes is optimally fitted to the intrauterine requirements. All other blood cells of these myeloid stem cell series also differentiate, though somewhat later, in the liver and in the bone marrow, respectively.

The lymphatic system is responsible for the defense of the body against antigens. The «microenvironment» of the thymus for the T cells (cell mediated immunity) and of the bone marrow for the B cells (humoral immunity), respectively, are crucial for achieving immunocompetence. The mature lymphatic cells emigrate afterwards into the secondary lymphatic organs, among which the lymph follicles of the mucous membranes, the lymph nodes and the white splenic pulp are included.

In contrast with the other organ systems the lungs begin their function as a gas exchange apparatus only at birth. During the pregnancy, however, they have an important function as an amniotic fluid-producing organ.

Prenatally, the air spaces are thus filled with fluid that, with the first breath, must abruptly be replaced by air. The perfusion relationships also change with birth in a dramatic fashion.

The following developmental steps are of importance for the future task of the lungs as gas-exchanging organ:

• a widely branched respiratory tree with a mucociliar cleaning mechanism
• a complex gas-exchange region with a short diffusion distance
• a thick net of capillaries that stands in close contact with the air spaces (blood-air barrier)
• a surface film (surfactant) that reduces the surface tension of the alveoli and thereby reduces their tendency to collapse

Morphologically one subdivides the lungs into two sections:

1. air-conduction part (air conducting respiratory passages)
2. gas-exchanging part (pulmonary parenchyma)

As a gas-exchange organ the adult lung has a surface area of ca. 140 m² (= a tennis court) which can only be achieved with an enormous differentiation of the embryonic tracheal tube into complex air spaces.
he bases for this are the asymmetrical dichotomous divisions, on average 16 generations purely air-conducting respiratory passages that end in the terminal bronchioli.
The following 7 generations of dichotomous divisions serve the gas-exchanging parenchyma. Through the differentiation of the parenchyma arises a very thin diffusion barrier between the air and the blood (blood-air barrier) that can be only 0.05-0.25 µm thick.
Functionally just as important is the differentiation - at the right time - of the type II alveolar epithelial cells that are responsible for the production of the surfactant.

The facial region develops ventral to the rostral neural tube from parts of the notochord, and the pharynx, which is surrounded on both sides by a series of aortic arches. Between these structures and the ectoderm there are a large number of neural crest cells (neurectodermal origin) and mesenchyma cells, which stem from the mesoderm. They have a tendency for segmental ordering and form the various sections of the facial anlage and the pharyngeal arches.

The face and the jaw stem from an unpaired forehead prominence (frontonasal process) and on both sides from the maxillary and mandibular processes, which stem from the first pharyngeal arch. Through differing growths of the individual processes the frontonasal process forms the upper half of the face (frontal process) and the nose while the middle part of the upper jaw and lip are formed by the medial and lateral nasal processes. The maxillary process fuses with the medial nasal process and forms the lateral part of the upper jaw and lip. The mandibular process forms the lower jaw, lip and the chin. Between the lateral nasal process and the maxillary process arises the nasolacrimal duct that connects the orbit with the nasal cavity.

The palate arises through the fusion of the unpaired median palatine process (primary palate) with the two lateral palatine processes (secondary palate).

The nose arises from the two nasal placodes in the frontonasal prominence. They subside and form two nasal sacs that are outwardly delimited on both sides by the lateral and medial nasal processes (the first forming later the nasal wings and the second the nasal septum). The nasal sacs (primary nasal cavity) open into the oral cavity via the posterior nasal orifices. Only somewhat later do these two nasal cavities widen towards the rear. They remain separated from each other in the middle by the nasal septum. The secondary palates separate them from the primary oral cavity.

The teeth form through the interaction between dental lamina (ectodermal ridge) in the upper and lower jaws and neural crest tissue. Initially they are cap-shaped and later bell-shaped. The ectodermal portion forms the enamel organ (ameloblasts) that forms the hard tooth enamel layer. In the interior the odontoblasts form from the neural crest tissue, which is responsible for dentin production. The salivary glands also stem from ectodermic sproutings.

The tongue arises from various anlagen in the pharyngeal floor region. From this the complicated innervation pattern of the tongue can be explained. The lingual musculature stems from the occipital somites that migrate into the tongue (lingual cord) with the glossopharyngeal nerve (cranial nerve XII).

In their interior all pharyngeal arches are delimited by the pharyngeal pouches and on the outside by the pharyngeal clefts. They form many of the various structures in the neck region.
From the 1st pharyngeal arch arise the upper and lower jaws. With mesenchyma of the 1st and 2nd pharyngeal arches that surrounds it, the 1st pharyngeal pouch and cleft forms the numerous small parts of the middle ear and the external acoustic meatus, respectively.
The 2nd, 3rd and 4th pharyngeal clefts obliterate and form the surface of the neck. Components of the 2nd to 4th pharyngeal arches form the skeleton, muscle and connective tissue portions of the neck.
Finally, from the 3rd and 4th pharyngeal pouches arise on both sides portions of the thymus, the parathyroid and the ultimopharyngeal body (only from the 4th pharyngeal pouch). The thyroid arises as an unpaired ventral sprouting from the upper pharynx (later base of the tongue) region (foramen cecum).

The intestines arise from a tube that forms from the endoderm. Cranially this tube ends at the oropharyngeal membrane and caudally at the cloacal membrane. It is subdivided into a foregut, midgut and hindgut. The midgut is connected with the umbilical vesicle. The differing development of the various intestinal sections is based on the local interactions with the surrounding mesenchyma (epithelio-mesenchymal interactions). Thus in the uppermost section, beside the thyroid, the primordia of the respiratory system, the pancreas, liver and gall bladder form as ventral sproutings.

The esophagus remains as a tube, obliterates, though, during the course of the embryonic development and only in the fetal period does it undergo a recanalization. It lengthens considerably, just like almost all intestinal sections, with the growth of the embryo.

The stomach appears quite early as a spindle-shaped widening. It is hung on a dorsal and ventral mesogastrium and through rotation reaches its adult position. Due to its large increase in length the midgut forms transiently a loop into the umbilical coelom (physiologic umbilical hernia). With the straightening up of the embryo in the late embryonic period the intestinal loops can move back again into the abdominal cavity, but experience a rotation (270 degrees) about their own axis. This leads to the characteristic arrangement of the colon around the loops of the small intestine. Parts of the mesenterium also coalesce later with the posterior abdominal wall so that the ascending and descending colon lies secondarily retroperitoneal. Just as with the esophagus the lumen of the small intestine also obliterates for a certain time in the early fetal period in order to be recanalized again late.

The pancreas, liver and gall bladder form as sproutings from the intestine.
The primordium of the liver arises at the level of the transverse septum. Through the enormous increase in size it extends, though, into the abdominal cavity but remains still connected with the transverse septum (diaphragm) by the area nuda. The liver primordium, together with the omphalomesenteric vessel, form the complicated sinusoid system of the liver.

The pancreas arises from two components, the ventral and dorsal pancreases. Through a shifting of the ventral part around the duodenum the two join and form dorsally the definitive pancreas in the mesogastrium, which somewhat later, adheres to the posterior abdominal wall. Through the coalescence of the mesentery in this region the pancreas finally also comes to be positioned secondary retroperitoneal.

In the entire intestinal tract many abnormalities can arise. They range from stenoses, atresias, duplications, fistulas, diverticula to abnormal rotations. Genetic disorders can also be responsible for malformations in this region.

The urinary tract develops from the 3rd week of the embryonic period from the intermediate mesoderm as well as from the urogenital sinus.

The kidneys develop from the 4th week in three steps:
As a first one, a cranial anlage, the pronephros, forms that then later atrophies in the 8th week and is never active functionally. It is followed by a further anlage from the intermediate mesoderm, the mesonephros, that is formed between the 6th and 10th weeks, but is only transitory, and the anlage of the definitive kidneys, the metanephros. They develop from a metanephric anlage (mesodermal origin) and the ureter anlage (that has its origin in the caudal part of the wolffian duct).

The urine-excreting part of the kidneys, the nephron, mainly arises from the metanephric anlage (glomerulus, proximal, intermediate and distal tubules), while the rest of the upper urinary tract (collecting ducts, calices, renal pelvis and ureter) develop from the ureter anlage.

The lower urinary tract differentiates from the cloaca between the 5th and 8th weeks in that it becomes subdivided by the urorectal septum. The ventral part of the cloaca forms the primary urogenital sinus, out of which the urethra forms in the lower part and the bladder in the upper part. The ureter anlage discharges into the upper posterior wall of the urogenital sinus. In males, the wolffian duct remains present and forms a connection to the genital tract in the lower part of the urogenital sinus.

The numerous induction mechanisms between ureter anlage and metanephric mesenchyma during the development of the renal system, as well as the ascent of the kidneys, originating at the level of the sacrum and moving up to the diaphragm at the end of the development, make it possible for a large number of abnormalities to arise. Many remain asymptomatic whereas others are not compatible with survival.

Sex determination takes place at the time of fertilization through the coupling of two gametes, either each with one X chromosome (XX in females) or such with an X and a Y chromosome (XY in males). Primarily, the male (female) phenotype is determined by the presence (or absence) of the Y chromosome with its genes, even though genes on other chromosomes are also involved. In addition to the genetic factors, hormonal regulation also plays an important role during the various developmental steps. During the first 6 weeks the genital system is sex-indifferent and it is only then that the gonads as well as the internal and external genitalia form under hormonal influence.

Two types of testicular cells are decisively important for the development of the male genitalia: firstly, the supporting cells (Sertoli) that surround the germ cells and form the antimüllerian hormone (AMH), which causes the paramesoneophric duct (Müller) to atrophy; secondly, the interstitial cells (Leydig) that produce testosterone, which is responsible for the differentiation of the male genitalia. On both sides of the epididymis the mesonephric duct (Wolff) forms the deferent duct, the seminal vesicle, and the ejaculatory duct and it opens into the urethra below the urinary bladder. The urethra as well as various accessory glands (prostate, bulbourethral and urethral glands) stem from the urogenital sinus. The penis arises from the genital tubercle and the urethral folds and the scrotum from the genital swellings.

In the ovarian cortex the primordial germ cells are surrounded by the follicle cells that come from the coelomic epithelium and form the primordial follicles. The development of the female genitalia is characterized by the atrophy of the mesonephric duct (Wolff) and the retention of the paramesonephric duct (Müller), out of which the fallopian tube, the uterus and a part of the vagina arise. The urogenital sinus forms the genital swellings, the urethral folds, the genital tubercle, the external genitalia (lowest part of the vagina, vaginal vestibule, labia majora and minora as well as the clitoris).

Early disruptions in the differentiation of the genitalia lead to hermaphroditism (e.g., by creating a mosaic of XX and XY cell populations). Other chromosomal aberrations (Turner or Klinefelter) also lead to abnormalities of the genital organs.

To the most frequent male genital abnormalities number the incomplete closure of the urethra, an incomplete descent of the testes, as well as inguinal hernias and hydroceles.
In women, fusion disorders in the region of the paramesonephric duct (Müller) lead to abnormalities in the utero-vaginal area.

Finally, proliferative tumors appear that stem from the primordial germ cells.

From a functional point of view, the nervous system can be subdivided into somatic and autonomous systems.  On the other hand, from an anatomic perspective, we distinguish between peripheral components, the nerves and ganglia, as well as central portions in the brain and spinal cord. The peripheral components contain the afferent (sensory) and the efferent (motor) connections between the receptors and the central nervous system, on the one hand, as well as the central nervous system and their target organs on the other. This module has been concerned mainly with the development of the central nervous system.

Due to the influence of the notochord and the prechordal plate (chorda-mesoderm complex) a thickening develops in the dorsal ectoderm, the neural plate (stage 7).  Between the 19^th and the 32^nd day of embryonic development, this neural plate is transformed into the neural tube (stage 10). From this, the brain and spinal cord emerge.  Already before the neural tube closes, cells of the neural crest migrate away (stage 9).  In essence, they end up forming the peripheral nervous system.
The transformation of cells of the surface ectoderm into neurectoderm cells is the result of the missing secretion of an inhibiting factor. There are, in addition, various signal molecules that are secreted and determine the polarity, the inner organization and the segmentation of the neural tube. The dorso-ventral differentiation manifests in the spinal cord in a separation of the sensory and motor components

From the 25^th day (stage 9), three vesicles can be distinguished at the rostral end of the neural tube: the prosencephalon, the mesencephalon and the rhombencephalon.
With the 5^th week, the further subdividing of the prosencephalon into the telencephalon and diencephalon and the rhombencephalon into the metencephalon and myelencephalon commences. Since at the mesencephalon no further subdivision takes place, 5 secondary cerebral vesicles result from it.

The nervous tissue arises in the region of the ependymal proliferation zone that borders on the inner cavity. In the first half of embryonic development, the glial cells and the nerve cells, the neurites, which only then become myelinized, arise from this layer.

Out of the central cavity system the cerebral ventricles and the central spinal cord channel that belongs to it emerge.

The spinal cord differentiates rapidly between the 6^th and 10^th weeks. Analogous to the formation of the mesoderm somites, a segmented structuring (metamerization) in the spinal cord also takes place. The sensory dorsal roots and the motor ventral roots bind themselves in each segment thereby forming the paired spinal nerves. This segmented organization becomes supplemented by the ascending and descending pathways that connect the brain and the spinal cord.

At around the 6^th week, on the side of the telencephalon two lateral vesicles appear out of which, later, the cerebral hemispheres develop (stage 14). In the dorsal part of the vesicle, the pallium, the cerebral cortex arises via radial and tangential migration into it by the various nerve cells. This cellular differentiation occurs during the first two trimesters of the development. In the metencephalon region, the cerebellum emerges from two different germinal zones: an interior one in the region of the ventricular zone of the alar plates and an exterior one in the rostral part of the rhombic lips.

The myelencephalon gives rise to the cerebral nerves IX to XII. In its structure the caudal segment of the myelencephalon resembles the spinal cord whereby, dorsally, the interfaces of the sensory pathways develop. Rostrally, the myelencephalon widens due for the forming of the roof of the IV^th ventricle. The choroid plexus that arises therein produces the cerebrospinal flui

At the metencephalon a floor (pons) and a roof (cerebellum) can be distinguished.  Through the dorsal spreading of the anterior rhombic lips the alar plate contributes to the formation of the cerebellum. The pontine nuclei also arise through the tangential cell migration out of the alar plate. Together with the basal plate they are involved in forming the nucleus regions of cerebral nerves V to VIII.

In the roof of the mesencephalon two masses of cells differentiate to become the superior and inferior colliculi, important interfaces for the visual and auditory pathways. In the mesencephalon tegmentum lie the nucleus regions of the cerebral nerves III and IV as well as the suprasegmental nucleus regions of the motor system (substantia nigra and red nucleus). Ventrally, the marginal zone of the mesencephalon becomes thickened through descending fiber systems to the cerebral peduncles.

In the prosencephalon the basal plate disappears in favor of the alar plate.

The diencephalon surrounds the III^rd ventricle and connects the telencephalon with the mesencephalon. In the diencephalon roof the choroid plexus of the III^rd ventricle arises as well as the epithalamus (epiphysis). On both sides of the III^rd ventricle the nucleus regions of the thalamus arise as polymodal interfaces in the service of the cerebral cortex. The subthalamic sulcus marks the boundary between the thalamus and hypothalamus. Out of the ventral region of the hypothalamus a hormonal gland, the hypophysis, as well as the eye and the optic nerve proceed.

In the lateral hemisphere vesicles of the telencephalon the strong growth of the dorsolateral proliferation zone and the migration of the nerve cells into the surface layers lead to the formation of the cerebral cortices. These expand laterally, dorsally, caudally and ventrally so that the cerebral lobes arise and through the formation of the sulcus lateralis, the insula is enclosed. In addition, the expansion of the cortex leads to the emergence of the cerebral convolutions and furrows.
The commissures of the telencephalon in the service of the olfactory and temporal cortex areas (rostral commissure), the hippocampus (commissure of fornix) and the neocortex (corpus callosum) develop out of the lamina terminalis.
The olfactory system forms through the mutual inductions between the ventral surface of the frontal lobe and the nasal mucous membrane.

The blood supply of the brain begins early during the formation of the neural tube in the 4^th week. In this, two input systems exist: the internal carotid artery and the vertebral artery.  The two vertebral arteries are connected to the basilar artery, which supplies the brainstem. They also release segmented spinal arteries into the spinal cord. The blood supply of the telencephalon occurs via 3 brain arteries, each of which is responsible for its own area. The venous return flow takes place independent of the arterial system via a sinus network within dura duplicates and flows into the internal jugular vein.

The musculature of the human body stems from the middle germinal layer, the mesoderm. One distinguishes three varieties of muscles:

• skeletal musculature
• cardiac musculature
• smooth musculature

The middle germinal layer forms through an inflow of cells with an ectodermal origin via the primitive streak and nodes. The mesoderm on both sides of the neural tube is called paraxial mesoderm. Out of it develops the musculature, among other things. Mesodermal cells more lateral form the intermediary mesoderm and completely lateral, at the transition to the extraembryonic structure, the lateral plate mesoderm forms. In the most cranial section of the embryo, in front of the prechordal plate, an accumulation of mesodermal cells form the cardiogenic plate, out of which the material for the cardiac musculature derives.

As an in between step, the somites form from the paraxial mesoderm. These represent pairs of epithelialized mesodermal segments to the left and right of the neural tube. They do not last long in this form and differentiate further into skeletal musculature (myotome), the skin (dermatome) and the skeletal axis (sclerotome).

The myotome cells go through various stages during their development to become skeletal musculature. The premyoblast is the first differentiated preliminary stage of the muscle cells, in that the cell bodies and the nucleus are lengthened. Responsible for this are several genes on chromosome 11. They belong in the family of myogenic regulatory factors (MRF) and activate the transcription of muscle-specific genes. The premyoblast then transforms itself into the myoblast that synthesizes the muscle-specific proteins actin and myosin. Subsequently, several myoblasts move together and form a syncytium, the myotubes. Initially, their nuclei are centrally located but with the beginning of neural activity they move to the periphery.

The smooth musculature forms in the surroundings of organs such as the trachea, the digestive tract, blood vessels, etc. Like with skeletal musculature the differentiation occurs through induction of muscle-specific genes in the corresponding myoblasts.