Eye development (vertebrates)

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As eye development of the vertebrate which will embryonic formation ( ontogeny ) of the organs of vision referred to. Research into these processes is part of developmental biology . The vertebrate eye shows clear differences between species in terms of structure and performance , while the phases of its ontogenesis have fundamental similarities. From a developmental point of view, the vertebrate eye is a prime example of an organ that is formed by a chain of ontogenetic triggering events. These so-called inductions are linked in such a way that the various components of the eye - such as the lens , cornea and retina - are in a strictly ordered and reciprocal relationship according to the sequence of developmental steps and thus appear as an overall system. Evolution critics have long assumed that these could only have arisen independently of each other and would consequently develop ontogenetically (individually) independently. The findings of the development of the eye have contributed to the fact that this view is obsolete today.

In vertebrates or cranial animals , the paired distant sense organs for olfactory perception and light perception are created in the head area in front of the mouth . The development of the eyes is initiated in the neuroectoderm and is based on furrows ( optical furrows ) on both sides that bulge into a pair of ocular vesicles ( optical vesicles ). These are two lateral protuberances of the anterior part of the neural tube , which arise from the embryonic forebrain ( prosencephalon ) in the area of ​​the later diencephalon ( diencephalon ). In the further course there is a series of tissue interactions, each of which leads to the formation of the lens from the surface of the ectoderm and to the lowering of the vesicle to the eye cup . While the outer leaf of the eye cup becomes the shading pigment epithelium, the inner leaf develops in complex processes into the retina with several layers of light or color-sensitive photoreceptor cells and their associated nerve cells. The connections between the nerve cell extensions and those with other parts of the brain are created in a self-organizing process using chemical signals. The formation of appendix organs such as eye muscles , eyelids and lacrimal apparatus are subordinate processes that will complete the development of the eye. Only long after birth is this completed with the coordination of eye movements , especially in living beings with binocular vision , and the optimization of visual acuity.

The evolution of the vertebrate eye

As the anatomy of the eye fossil is not known in detail and also the fossil record of the earliest vertebrates and their immediate ancestors is virtually unknown, the statements made below are based on the evolution of the vertebrate eye on

  1. comparative anatomical studies of the structure of the eye (also at the molecular level) in the individual recent large groups of vertebrates
  2. molecular genetic studies of the relationships between these vertebrate groups
  3. the use of the molecular clock , which makes it possible to assign the evolutionary steps to a period in the past
  4. comparative studies on embryonic development in the individual recent large groups of vertebrates

The evolution of the vertebrate eye can be roughly divided into six phases (Fig. 1). In a first phase, simple bilateral animals developed rhabdomer-like (brush-shaped) and ciliary (equipped with eyelashes) photoreceptors with corresponding early forms of the visual pigment protein opsin as early as 600 million years ago . Light-sensitive dyes (chromophores) are integrated into these visual pigments, which are decisive for the perception of light in animals ( phototaxis ). The receptors may have been concentrated in so-called eye spots ( ocelles ) or distributed over the whole body.

In a second phase between 580 and 550 million years ago (late Proterozoic ), the immediate ancestors of the first vertebrates had developed advanced ciliary photoreceptors with the corresponding opsin protein. These were probably very similar to the photoreceptors of the closest relatives of the vertebrates living today, the lancet fish ( Branchiostoma ) and those of the lancet fish-like larvae of the tunicates (Tunicata).

In phase three, about 550–530 million years ago (early Cambrian ), there was already a type of photoreceptor with an outer membrane and an output suitable for graduated signal transmission at the synapse . The tissue of the nerve node in the head region (“brain”) formed protuberances (vesicles, ocular vesicles) with photoreceptors on both sides. These vesicles then began to invade again in the shape of a cup, with the inside of the cup representing the earliest form of the retina . The invagination of the vesicle was accompanied by the attachment of an early form of the retinal pigment epithelium to the "proto-retina". In addition, the lens placode was created , homologous to the embryonic lens system of higher vertebrates of the same name. The lens placode, however, initially only prevented the pigmentation of the outer skin of the head overlying the eye vesicle, so that the outer skin remained translucent in these areas. This early eye, about 530 million years ago, still without the imaging capabilities of the retina, can be compared with that of the recent hagfish (myxinoidea), the most primitive recent vertebrates.

In the next, fourth section about 530–500 million years ago (middle Cambrian), five different novel photoreceptor cells, the cones , each with its own ciliary opsin, as well as bipolar cells and novel retinal ganglion cells (so-called "biplexiform retinal ganglion cells") evolved as a prerequisite for the more demanding signal transmission to the optic nerve. Bipolar cells and ganglion cells are organized in a three-layer nerve structure within the retina. By invagination of the lens placode in the optic cup and subsequent constriction resulting lens . Accommodation and the iris (and thus the possibility of a limited change in the size of the pupil ) were added later, as well as extra-ocular muscles with nerve connections for eye movement . During this period, around 500 million years ago, there was already an eye that was basically comparable to that of almost all modern vertebrates. It had the design of a simple camera, so could see images and was the eye of the modern lamprey ( Petromyzon ) most similar.

In phase five, 500–430 million years ago (late Cambrian to late Silurian ) myelin evolved , which ensures faster signal transmission throughout the nervous system. There is also another new type of photoreceptor, the rods , which enable vision in weak light. With these, the visual pigment rhodopsin , which is characteristic of vertebrates, appeared . The iris became highly contractile and could now optimally adapt the pupil size to the light conditions ( adaptation ). On the inside of the eyeball, muscles developed for the lens, which allowed for improved accommodation. This already relatively highly developed eye probably identified the armored, jawless fish (" Ostracodermi "), which are now extinct, and it was probably also very similar to the eye that is found in many modern fish, and thus in jaw-bearing vertebrates ( Gnathostomes ).

During the sixth and final phase, which began about 430 million years ago, u. a. also the basic version of the eye of terrestrial vertebrates (tetrapods). In the course of the numerous adaptations of the fish-like vertebrate organism to life outside the water, which began about 375 million years ago (late Devonian ), the lens assumed an elliptical shape in cross-section . This was necessary because the light is refracted more strongly when air passes into the cornea than when water passes into the cornea. The eyelid was created to protect the eyes from drying out in the air .

In summary, it can be said that the vertebrate eye of most Gnathostomes required an evolutionary period of around 200 million years from the simplest predecessor forms, only distinguishing between light and dark, to the modern, high-resolution, colored images capable of seeing high-resolution, colored images. All the basic features that also characterize the human eye could already have been present after another 50 million years, at the end of the Devonian. More than 200 million years later, a number of endothermic and therefore nocturnal vertebrates (e.g. owls and cats) reduced some of the photoreceptors that were unnecessary for this and adapted their retinas to night vision in other ways . In addition, specializations of the eye with corresponding modification of the basic gnathostome type also occur in other lines of development of the jaws.

The eye as a prime example of networked triggering processes

Fig. 2 Important chains of developmental physiological triggering processes (induction chains ) in the development of the vertebrate eye

A whole cascade of organized tissue interactions in the form of consecutive and networked triggers ( inductions ) is required for the development of the phenotype to start and proceed in the correct order (Fig. 2 and 12). There are three specific DNA sections at the beginning of the chain. They each contain a type of gene that is important for the entire further development of the eye, which is called the switch gene, master gene, master control gene or transcription factor . These are the genes Rx1 (retinal homeobox gene), Six3 ( lat.sine oculis ) and above all - measured by their frequent occurrence in specialist literature - the gene Pax6 ( paired box 6 gene ) discovered by Gehring in 1995 .

Fig. 3 Mouse with eye (above) and without eye (below) as a result of suppressed Pax6 expression

Furthermore, the induction of the lens placode (lens induction) and thus the formation of the lens is driven by two main factors, firstly the presence of the expression of Pax6 in the epidermis of the head and secondly the presence of the specific ectoderm tissue. The steps associated with Pax6 and other genes in the early development of the lens eye are deeply anchored in evolutionary history and often agree across species. Pax6 itself is completely identical in mice and humans. The genes Pax6 , Rx1 and Six3 mentioned are a necessary and sufficient control loop for eye induction in vertebrates. By using Pax6 from the mouse, it was initially possible to induce ( ectopic ) eyes in the fruit fly in an experiment . This spectacular experiment, in which the function of the fly's eyeless gene, which is homologous to Pax6, was fully demonstrated, demonstrated the high conservation of Pax6 . Later, the same was at least partially achieved in vertebrates, including chickens (1995) or using Sox3 in clawed frogs ( Xenopus laevis ) ( 2000 ). In these experiments, ectopic lenses or placodes developed. The fact that the experiments did not lead to such complete results as with the fruit fly suggests that vertebrates are more complex. In any case, vertebrate ocular development does not occur at all if Pax6 is suppressed (Fig. 3).

The three master control genes mentioned form a stabilizing network that triggers new inductions and activates hundreds of other genes. There are 2000 genes in the fruit fly eye. The pigmentation of the iris alone , i.e. the color of the eyes, requires at least 16 different genes. Further inductions follow in the course of eye development. They each initiate extensive developmental steps, including many downstream genes, such as the formation of the lens and the cornea (Fig. 2).

The role of the Pax6 gene

The extreme special position of Pax6 as the master control gene for eye development granted after its discovery can be reassessed after 20 years. The specialty of Pax6 as a master gene speaks first of all that it is expressed early on the one hand, namely already in eye stem cells, and on the other hand in many tissues during the entire eye development, namely in fruit flies, humans and squid. Eye development is assumed to be independent in these species from different animal phyla. Pax6 can therefore be considered preserved since a common predecessor. Second, reducing its expression leads to decreased eye size in Drosophila , mouse, and humans . Third, Pax6 mis-expression in certain tissues, e.g. B. cause ectopic eyes in the Drosophila wing or leg .

The following facts speak against an outstanding or even sole master gene position of Pax6 in eye development: First, the elimination of Pax6 or that of the homologous gene Eyeless in Drosophila , which also belongs to the Pax6 family and has a comparable function in the fly, does not lead alone to the loss of the eye, but also of other parts of the brain, in extreme cases in Drosophila to total head loss . Second, other genes besides Pax6 play key roles in early eye development, such as the aforementioned Rx1 and Sine oculis ( Six ), Eyes absent (Eya) or Dachshund (Dach). These genes can also induce ectopic eyes. Their loss of function also leads to the loss of the eye. They thus show similar master control gene properties as Pax6 .

In summary, from the current point of view, the well-known cross-tribal characteristics of Pax6 are less questioned. However, they are being put into perspective compared to the capabilities of other master genes today. According to the current state of science, one must therefore speak of the evolutionary conservation of the regulatory network of a whole group of genes.

Phases of eye development

Early initiation of the development of an eye field

Fig. 4 Eye field in the clawed frog, frontal view. Uniform field in the neural plate of the gastrula, not yet divided between the left and right sides. (Gene expression marker purple, diameter of the gastrula 1.8 mm.)

The vertebrate lens eye can be seen as a sensory organ that grows out of the brain . At the end of gastrulation , the first course for the development of the eye is set. This is still the case at an early stage of embryonic development, when the formation of the three cotyledons, endoderm , mesoderm and ectoderm (inner layer, middle layer, outer layer) comes to an end. In the eye, as in the other sensory organs, the ectoderm is the essential germ layer from which the structures develop. In humans, these first steps start on the 17th day of pregnancy.

The development of the shoe sole-shaped neural plate on the gastrula (Fig. 4, light gray area), from which the neural tube (Fig. 4, vertical median strip) and later the brain and spinal cord arise, is triggered ( induced ) by the mesoderm below , and a uniform eye field is initially formed on this flap (Fig. 4, purple). The mentioned switch genes Rx1, Six3 and Pax6 are essential for the initiating steps. During the formation of the neural tube, the eye field divides into two outer eye domains, controlled by the Sonic hedgehog ( Shh ) gene , which is activated in a midline between these two domains and suppresses Pax6. Sonic hedgehog explains why the vertebrate has two eyes. If it is not expressed at this crucial point, cyclopia develops . A lack of activation (expression) of the switch genes mentioned leads to the loss of eye formation.

Eye vesicle and lens placode

Fig. 5 Mouse eye 14.5 days after fertilization (E14.5) with Pax6 expression (green). Approximately corresponds to phase 3 in Fig. 8
Fig. 6 Development of the vertebrate eye - phase 1: bulging of the neural tube and formation of the optical vesicles (humans: 4th week)
Fig. 7 Development of the vertebrate eye - phase 2: invagination of the surface ectoderm, reshaping of the vesicle into an eye cup, formation of the lens placode and formation of the inner and outer retinal layer (humans: 5th week)
Fig. 8 Development of the vertebrate eye - phase 3: Formation of the lens, vitreous body and cornea (human separation of the lens body : 6th week)

As a result, around the beginning of the second month of pregnancy in humans, the anterior neural tube bulges out in the eye fields and grows out as optical vesicles from the diencephalon (Fig. 6), known as the eye stalk . Accordingly, the excitation received through this first reaches the diencephalon , processing takes place in the cerebrum .

The eversion of the ocular vesicles is based on individual cell migration . As was first discovered in fish, the Rx3 protein gives the eye precursor cells molecular signposts. They provide these cells with information on how to move from the center of the brain towards the eye field, where larger accumulations of these cells occur. The outgrowing optical vesicle interacts with the outer layer and, as a new important induction step, triggers the formation of the lens placode, a thickening of this ectoderm and indentation of the eye pit (Fig. 5 and 6). Without the vesicle (with the exception of amphibians) there would be no thickening and no lens. The surface ectoderm is increasingly prepared for prospective lens formation through various mesodermal signals and signals from the optical vesicle. The tissue is initially designated as competent for lens formation and then becomes lens- specific in further steps . After contact with the vesicle and its signals, the tissue can only become a lens. Only the upper skin of the head ( epidermis ) is thus able to react to signals from the optical vesicle. Empirical experiments have shown that a vesicle that is implanted in a region other than the head ectoderm and allowed to grow there does not lead to lens formation. But even transplanted surface ectoderm of the head does not lead to a lens if there is no contact with the optical vesicle.

The thickening of the ectoderm leads to the reshaping of the vesicle into a cup, the eye cup (Fig. 7). Using appropriate induction signals, this ensures that the initially not yet transparent lens is created. After their initial formation, the surface ectoderm closes again over the vesicle. The lens vesicle separates from the ectoderm and sinks into the depth (Fig. 8).

Lens and cornea

The early lens, the lens vesicle emerging from the lens placode, is initially a hollow ball made of surrounding cells (Fig. 9.1). Each of these cells contains a nucleus with chromosomes and DNA. The anterior side faces the outside and the posterior side faces the inside of the eye (Fig. 9.2). The cells are surrounded by a capsule with proteinaceous material (only shown in Figs. 9.1 and 9.6). In a first step, from the fifth week in humans, the posterior cells extend into the cavity (Fig. 9.2, blue-gray). They form primary lens fibers , the later lens nucleus . Layering around the central nucleus always takes place from the lens equator (Fig. 9.4). When elongated, these fibers form several proteins called crystallines . These fill the cavity of the lens and later form the main components of 3 types and 90% of all proteins in the lens. First, they make up the lens fibers. As a result, the lens fiber cells break down their nucleus as well as other organelles , including the energy centers ( mitochondria ) (Fig. 9.3, blue). This drastically reduces the cell metabolism and minimizes the scattering of light . As usual, this process does not lead to programmed cell death ( apoptosis ). As a result of these processes, the lens cells cannot and do not have to renew themselves until death.

The anterior cells remain as a single layer of cells on the outer surface of the lens (lens epithelium), even with the fully developed lens. They continue to divide, with secondary lens fibers developing at the upper and lower ends in humans from the seventh week (Fig. 9.3, red). These lens fibers become very long and overlap the lens in concentric rings like onion skin in many layers. For this purpose, new secondary lens fibers always grow from the above-mentioned positions above and below the lens (Fig. 9.4), displace the previously formed secondary lens fibers inward, while new secondary lens fibers are generated (Fig. 9.4, brown), which are equally grow around the lens. The anterior outer layer continually forms replenishment material for this process through cell division. The lens can grow as new rings continue to form (Fig. 9.6). During the entire period of prenatal lens development, a vascular network containing blood vessels is spread over this posteriorly and laterally, the tunica vasculosa lentis , which only disappears shortly after birth.

The formation of new secondary lens fibers continues throughout the life of the organism. The lens no longer enlarges significantly, but increases in density. The developed lens contains a nucleus from early cells (Fig. 9.6, light blue). With increasing age, the elasticity of the lens decreases and it loses its ability to accommodate more and more. The finished lens is the only organic tissue made up of completely transparent, living cells.

Fig. 9 Stages of lens development
Fig. 8.1 Light microscopic sectional image of the brain vesicle and the ocular cups with lens system. Chicken embryo ( hematoxylin-eosin stain )

The lens can be regenerated in a salamander . This happens through transdifferentiation , a gradual regression of cells on the mesodermal edge of the iris to an earlier state (Wolff lens regeneration). The lens can be regenerated up to 18 times. Certain tissues of the iris and the neural retina can also be regenerated in salamanders .

The next process after the lens induction is another induction, this time the lens with the surface ectoderm. There it leads to a new thickening, the cornea (Fig. 5 and 8). In contrast to the cells of the lens, corneal cells have an extremely short lifespan and also renew themselves weekly after birth. The cornea is heavily penetrated with nerves. The front edge of the cup becomes the pupil . The cornea results from a transformation of the surface ectoderm into the anterior epithelium. The choroid ( choroid ), sclera ( sclera ) arises from the mesodermal mesenchyme of the head region. With the formation of the dermis, blood vessels can begin to develop that run through the retina.

Retina

Fig. 10 Cell types in the three layers of a mammalian retina - light enters from the left, the layers rich in cell nuclei are highlighted in white. v. l. Right: white: ganglion cells and their axons, gray: inner layer, white: bipolar cells, yellow: outer layer, white: photoreceptors, light brown: photoreceptors outer segments.

Before the retina differentiates , the tissue consists of an array of undifferentiated retinal progenitor cells. Similar to the previous phases of vesicle or lens induction, ordered steps of cell differentiation have to be established. For this purpose, all of these retinal progenitor cells express a common suite of transcription factors , which are genes that in turn express other genes. These are Pax6, Six3, Six6, Lbx2, Hes1. At this stage , the cells are still multipotent stem cells , which means that they can still differentiate into different target cells. In addition to the partially light-conducting Müller cells, these later become mainly the photoreceptor cells and various types of nerve cells, which they interconnect as horizontal cells or form the signal flow downstream, such as bipolar cells , and modulate their extensions , like amacrine cells , before it reaches the ganglion cells of the retina can then transmit signals from the eye to other areas of the brain. The mechanisms that ensure accurate cell differentiation for the development of the retina are gene activities both from the optical vesicle ( intrinsic ) and from mesenchymal regions outside the eye ( extrinsic ). Here, play fibroblast growth factors (FGF) an important role. A self-amplifying sonic hedgehog expression wave that “sloshes” through the ganglion cell layer causes the ganglion cells to be the first to differentiate. Another Shh wave, which is expressed across the inner layer, gives the starting signal for the differentiation of further neuronal cells in the retina. Both discoveries were made in the zebrafish.

The wall of the eye cup now consists of an outer and an inner sheet, in which further retinal layers will later develop (Fig. 7 simple, Fig. 10 inner layer in more detail). The thin, outward-facing sheet (Fig. 8) forms the retinal pigment epithelium , which darkens, absorbs light and serves to regenerate the sensory cells. The structure of the thicker inner sheet is described in more detail below. This neuronal retinal layer consists of nerve cells and is divided into further inner and outer sublayers (Fig. 10). In the course of development, another middle sublayer with the bipolar cells of the retina forms in the neuronal layer . Its task is to collect the information from the light-sensitive photoreceptors (rods and cones), to weight it and to forward it to the ganglion cells of the retina inwards (Fig. 10 left). In summary, in the retina of the eye, similar to other sensory organs such as the ear, essentially three layers of cells, one on top of the other, develop here: receptor cells, bipolar cells and ganglion cells, whose neurites project to regions of the brain. This arrangement applies equally to humans as it does to other vertebrates.

The formation of cones and rods is made on the outer side of the inner layer (Fig. 10 right, nuclei of the photoreceptors before white background layer, light sensitive, elongated extensions before brown background layer). The three different types of cones in humans are used to differentiate between the shades of light. The rods convey the intensity as brightness alone. Since humans only have one type of rod, no color impression can arise in them at dusk. Nocturnal vertebrates have developed more rod types.

Most of the complex retinal development in humans takes place in a coordinated cell growth wave from the middle of the 3rd month to the 4th month. Then the optic nerve is completely myelinated for adequate signal transmission . The yellow spot (macula lutea) with the greatest density of special cells (cones) only begins to develop after 8 months. It continues to grow beyond birth. After about five months, the nerve connection between the eye and the brain is complete. As early as the 7th month of pregnancy, the embryo shows certain forms of eye movements , the so-called Rapid Eye Movement (REM), which supports the synchronization of the retina with the visual cortex in the brain and also occurs after birth in certain phases of sleep, the meaning of which is still being researched (see REM sleep ).

Light-facing (inverse) position of the photoreceptors

The vertebrate eye is considered to be part of the brain because its first system emerges from it. This is not the case with the octopus , for example , which is not a vertebrate but a cephalopod, in which the eye is created by the invagination of the outer surface. The development process in vertebrates with an inverted retina has several consequences: First, the internally bundled optic nerve leading to the brain generates a blind spot, since there are no light-sensitive sensory cells at the point where it emerges from the eye. Second, the nerve fibers, nerve cells and blood vessels lie on the inside facing the light, so the light has to pass through them before reaching the photoreceptors. Thirdly, the long photoreceptor processes of the cones and rods are directed outwards towards the pigment epithelium - away from the light. The light must therefore both pass through the overlying layers and, unscattered, the photoreceptors themselves before it hits their light-sensitive outer segments (Fig. 10). With the octopus the way is easier; with him the light hits the receptors directly.

With otherwise identical and equally well-developed components of the eye, the inverted retinal structure of the vertebrate indicates a “suboptimal” evolutionary solution. The octopus could possibly see better in low light, as there are fewer obstacles in the way of the incoming light signals. According to evolutionary theory, however, evolutionary solutions do not have to be perfect, they just have to be so good that the species is sufficiently well adapted to its respective environmental conditions to be able to survive. The inverted lenticular eye in night birds is adapted to seeing in the dark by improving the retinal properties.

The structural differences in vertebrate and octopus indicate, at least in the case of the structural element of the retina, an independent, convergent history of development of these eye types. On the other hand, there are genetic bases that match the switch genes, or at least similar and thus homologous. The developmental genetics of the eye with the simultaneous reference to convergence and homology thus provide ambiguous indications of its evolutionary history. In other words: photoreceptors or gene networks that initiate the eye can have arisen once or several times; certain structural elements of the eye, such as a lens or multi-layered retina, have arisen several times independently in each case.

Visual pathway and its components

Fig. 11 Routing and partial crossing of the nerve pathways from the eyes to the brain

In addition to the rods and cones as photoreceptors in the eye, the retina also forms several million nerve cells for initial information processing. In order for the eye to function as a sensory organ, the incoming light information must be passed on to the brain as "higher-order evaluation stations". First, ganglion cells form on the inner retinal layer (Fig. 11, left). These cells form nerve fibers ( axons ) that penetrate the retinal layer and subsequently have to search for and find specific target areas in the brain. The control of this topographical target achievement is a self-organizing process (axon guidance). Complicated chemical processes are responsible for this: molecules in the retina and in the midbrain (tectum) form graded chemical gradients. The concentration gradients created by diffusion help to direct the growth direction of the axons. The axons are bundled at the blind spot and, in mammals, are carried on from there as the central nerve cord, the optic nerve, via the visual pathway with various neuronal structures to the visual center (visual cortex) (Fig. 11). After an intermediate station, you first reach the primary visual center for preprocessing and then the secondary visual center. In this way, there is a partial junction of the optic nerves ( optic chiasm ). The optic nerve cells of the left eye reach the primary visual center of both the left and right hemispheres of the brain. The same applies to the nerve cells of the right eye. In the reception area of ​​the brain, the nerve cells that are already arriving in several individual strands must be fanned out further so that precise processing is possible. Depending on the place of origin, the axons open into different, narrowly defined areas. The process is called retino-tectal projection . It is largely controlled by ephrins (gradients) and ephrin receptors . A map on the retina corresponds to a copy of this map in the brain. In non-mammals (fish, amphibians, reptiles and birds) a complete crossing of the nerve pathways is formed. All axons on one side of the eye are guided to the opposite side of the brain. The effect of the junction of the optic nerve can be demonstrated experimentally in the clawed frog Xenopus laevis by removing an eye cup and reimplanting it the other way round. The retinal regions in the midbrain are assigned uncrossed. The animal moves its tongue in the wrong places when foraging and only learns correct orientation over time.

Appendage organs and pupil

External eye muscles

Fig. 12 Somites (red), "ursal segments", some of which arise from thusomeres and all from the mesoderm, in a human embryo (back view). From their muscle segments ( myotomes ) arise u. a. the outer eye muscles lettering in Dutch

In vertebrates, the internal and external eye muscles are differentiated depending on their function and location . The external eye muscles responsible for eye movements arise together with Tenon's capsule (part of the ligamentous apparatus) and the fatty tissue of the eye socket ( orbit ). They are common descendants of the embryonic connective tissue ( mesenchyme ) that surrounds the eye vesicles and are formed from so-called thusomeres , certain mesoderm segments of the trunk area of ​​the embryo that grow on both sides (Fig. 12). The eye muscles later supplied by the oculomotor nerve ( upper straight muscle , lower straight muscle , inner, nasal, straight muscle and lower, oblique muscle ) come together with the eyelid lifter from the foremost two thusomeres 1 and 2, the upper oblique muscle from the third and the lateral straight muscle , as well as the retraction of the eye , which is no longer present in humans , from the fifth thusomer. The muscle cells from the myotomes of the somites migrate to their target areas in the eyes, where the muscle structures are then formed.

Further development is controlled by three growth centers, each of which is assigned a nerve. This results in the later motor nerve supply ( innervation ) of the eye muscles through the three cranial nerves oculomotor nerve (III), trochlear nerve (IV) and abducens nerve (VI). The development of the external eye muscles depends on the normal development of the eye socket, while the development of the ligamentous apparatus is independent of this. The eye muscles develop late in humans, not until the fifth month. Complete coordination of all forms of eye movements does not take place until after birth in infancy and usually takes place between the 2nd and 4th month of life.

Eyelids

In the 7th week the eyelids appear in the form of two skin folds that grow from above and below the eye and are closed between the 10th week and the 7th month due to the adhesion of their epithelial edges. The eyelashes develop on their edge , and the meibomian and minor glands develop as epithelial cords sprout into the mesenchyme . In this phase, the nictitating membrane known as the “third eyelid” also develops in the nasal corner of the eyelid. At the same time, the conjunctiva forms from the head mesenchyme .

Lacrimal system

In the 9th week of pregnancy, a series of epithelial sprouts pulls out of the lateral conjunctival sac into the underlying mesenchyme, from which the lacrimal glands are formed. They are divided into two appendages of different sizes by the tendon of the levator palpebrae superioris muscle. The draining tear ducts develop from the so-called tear-nasal groove, which forms on the outer nasal wall around the 7th week of pregnancy . Their erosion begins in the 3rd month of pregnancy, but their discharge points only open in the 7th month of pregnancy.

Pupil and inner eye muscles

Fig. 13 Phases of human eye development before and after birth

Around the 8th week of pregnancy, the rounding of the eye cup opening causes the pupil to form in humans , which, among other things, reacts dynamically to the incidence of light as a pinhole . The inner eye muscles, the sphincter pupillae and the dilatator pupillae muscles, develop between the eye cup and the surface epithelium . Your cells come from the ectodermal epithelial cells of the eye cup. The ciliary muscle , which continuously adjusts the eye to the different object distances , arises from the mesoderm within the choroid and is regarded as a derivative of the neural crest.

In the final stage of pregnancy, pupillary reactions occur in the embryo, which contrary to previous beliefs are already possible and necessary in the uterus . Dilation of the pupil by the responsible dilatator pupillae muscle , which is controlled by the sympathetic nervous system , part of the autonomic nervous system, can therefore also be an expression of emotional excitement. The light reaction controls the number of neurons in the retina. At the same time, it regulates the development of blood vessels in the eyes. The photons in the womb activate a protein melanopsin in the mouse embryo , which sets the normal development of blood vessels and neurons in motion.

Further development after the birth

The development of the eye is not yet complete at birth. It did not reach its full size until the beginning of puberty and undergoes a number of changes in the first year (Fig. 13). This enlarges the field of vision ; the lens, the macula and the pigmentation of the iris experience structural improvements. Complete coordination of all forms of eye movements and thus the development of binocular vision takes up to a few months after birth. Many cells of the corpus geniculatum laterale , part of the visual pathway, are not yet able to react to the light stimuli coming from the ganglion cells of the retina. The visual acuity (vision) is also due to a more unstable central at birth fixation not yet fully formed. In fact, the visual acuity develops until around the age of 10.

pathology

Cyclopia

Probably the most spectacular malformation is the already mentioned cyclops eye, the cyclops . If the two eye systems do not diverge, a conglomerate of eye parts forms in the middle of the upper half of the face (Fig.). Because of the associated brain malformation, the fetuses are unable to survive. Incomplete closure of the embryonic eye cup leads to the formation of gaps of varying sizes, the iris, choroid and retinal colobomas . Viral diseases in the mother in the first trimester of pregnancy, but also the use of some medications, can lead to developmental disorders. The clouding of the lens, along with other damage caused by rubella infection, is known in the 4th to 8th week of pregnancy, i.e. in the phase of lens development. It is not uncommon for humans to have persistent remnants of the pupillary membrane as usually harmless inhibition malformations. Bleeding from it has only been observed in isolated cases. They are also described in vertebrates (rats, rabbits).

Special features in selected vertebrates

Fig. 14 Retroreflection in cats' eyes through the tapetum lucidum on the retina

Vertebrate eyes have to meet specific requirements, for example for perception in the dark (cats, night birds) or sharp vision at great distances (birds of prey). Cats in particular, but also dogs, horses and cattle, for example, have developed a retroreflective layer behind or in the middle of the retina as a residual light amplifier for increased night vision , the tapetum lucidum (mirror eye) (Fig. 14). Other developmental differences emerge in birds of prey. Your eyes are relatively large, which enables a high incidence of light and thus a large image of the visual object on the retina and in the brain. The larger-area division of the fixed object over a higher number of retinal cells leads to a more detailed image.

The eyes of the birds of prey are formed on the front of the head, i.e. frontal, which enables the simultaneous perception of an object with both eyes. If this arrangement permits simple binocular vision , this is the prerequisite for spatial vision, as is the case with humans.

For optimized sharp vision, birds of prey develop highly specialized, neuromuscular accommodation . Here, fine ciliary muscles adapt the curvature of the lens to changing object distances. In addition, birds of prey develop a second, lateral visual pit in the retina in addition to the central fovea . Here, as in the central visual pit, there is a compression of cones. After all, all birds have a comb-like eye fan within the vitreous humor , the pecten oculi . This structure, with its narrow capillaries, ensures increased blood flow and nutrient supply to the retina.

Fig. 15 Quadruple eyes with split-looking eyes for simultaneous, equally good above and underwater vision

Humans see sharply at different distances by changing the radius of curvature of the lens and thus shifting the focus. Snakes and fish achieve the same effect by changing the distance from the lens to the retina. A special muscle enables fish to pull the lens from the resting state towards the retina, snakes to the front. Snakes do not have an eyelid . Rather, the surface of the eye is covered by a transparent scale. There are also differences in color perception . While humans develop three types of cones (trichromatic vision), most mammals only develop two types of receptors (dichromatic vision), while reptiles and the birds that have emerged from them develop four (tetrachromatic vision), and pigeons even five. Unlike humans, birds can see UV light . Sharks, whales, dolphins and seals are color-blind and only have one green-sensitive cone type.

The migration of one of the two eyes in flatfish is unique in the eye development of vertebrates . Here, an eye can migrate past the dorsal fin or through its base to the later upper side of the body during early growth. The hike can be on the left side ( turbot ) or on the right side ( plaice , sole ).

Fig. 16 Mute turtle - horizontal central line of the eyes when looking forward
Fig. 17 Mute turtle - horizontal central line of the eyes when looking upwards (same individual as in Fig. 16)

Some aquatic turtles, including the false map turtle (Graptemys pseudogeographica), can rotate their eyes around an imaginary axis that connects the pupils (Figs. 16 and 17). As a result, the central line of the eyes usually remains aligned with the horizon, even if the animal swims up or down and looks in the swimming direction. The retina has the highest density of receptors at the level of the black central line, so animals living close to the ground or in the water are best adapted to see along the horizontal line. This unique development is presumably coordinated by the sense of balance in the brain (vestibular organ), which controls specific eye muscles. A major challenge is the adaptation to the eyes of vertebrates, which have to see well both under and above water, such as the four- eyes . His cornea develops in two parts: the upper half is strongly curved for seeing above water, the lower half only very slightly curved for seeing under water (Fig. 16). This takes into account the different refractive powers of air and water and at the same time enables good vision in air and water. The retina of the quadruped eye also develops in two parts. The side responsible for seeing in the air has twice as many cones as the side responsible for seeing in water.

Chameleons develop several outstanding features in their eyes. These can be moved independently of one another. It is assumed that there is an independent and separate processing of the information in both eyes in the brain. Chameleons also achieve an additional pinhole camera effect through the small eye opening , which allows them to focus on a kilometer. Their focusing speed is about four times faster than that of humans. Other special features of vertebrate eyes are the spherical lens in fish, which is focused at a short distance when at rest, multifocal lenses in some types of cats, the inclination of the retina to the lens in horses, which causes a varifocal effect, or the protective nictitating skin in frogs, birds and dogs, rudimentary too in the nasal corner of the eye in humans. Developmental processes and genetics of the eye components and differences described here in vertebrates have only been little researched.

Chronology of Scientific Discoveries in Eye Development

year Researcher discovery
approx. 350 BC Chr. Aristotle The formation of the eye and other organs is not predetermined ( preformation ), but they arise one after the other, like a chain reaction. Connection of the eye to the brain, eye as part of the brain (observed in the chicken embryo). Eye-brain connection, however, not recognized as a sensory physiological connection.
1660 Edme Mariotte Blind spot
1817 Christian Heinrich Pander The optical vesicle originates from the forebrain
1830 Emil Huschke Lens is formed from surface ectoderm cells
1830 Emil Huschke Optical cup is formed from the vesicle
1850-1855 Robert Remak Lens skin develops from the lens vesicle
1861 Albert von Kölliker Retina is made up of two layers of the optical cup
1875 Johannes Peter Müller The fibers of the optic nerve start in the retina and grow into the forebrain
1895 Gustav Wolff First description of lens regeneration through tissue transformation from the iris in newts
1920 Hans Spemann The lens induction occurs through the optical vesicle
1963 RW Sperry Growth and targeting of the ocular nerve fibers
1992 RM Grainger Lens induction steps: From lens competence to lens specialization of the ectoderm
1995 Walter Jakob Gehring Discovery of the Pax6 gene as a switch gene for all types of eyes
1999 Robert L. Chow et al. Pax6 gene has been identified as an inducer for the eye in vertebrates
2002 AK Knecht & M. Bronner-Fraser Induction of the neural crest as a multigenetic process
2002 SW Wang et al. Regulation of retinal cell differentiation
2003 M. Zuber et al. Gene regulation network for eye formation relativizes the unique position of Pax6
2006 M. Rembold, F. Loosli, J. Wittbrodt Individual cell migration in the brain causes the formation of the optical vesicle.
2008 P. Betancour, T. Sauka-Spengler & TM Bronner-Fraser A gene regulation network controls the formation of the neural crest
2013 S. Rao et al. Light reflections in the womb activate melanopsin to form vessels and neurons

See also

literature

  • Jan Langman (first), Thomas W. Sadler: Medical Embryology. Normal human development and its malformations. 10th edition. Thieme Verlag, Stuttgart 2003, ISBN 3-13-446610-4 .

Web links

Commons : Eyes  - collection of images, videos and audio files
Commons : Embryology  - collection of images, videos and audio files

Individual evidence

  1. ^ A b Trevor D. Lamb, Shaun P. Collin, Edward N. Pugh Jr .: Evolution of the vertebrate eye: opsins, photoreceptors, retina and eye cup. In: Nature Reviews. 8, 2007, pp. 960-975.
  2. ↑ a b c d e Werner A. Müller, Monika Hassel: Developmental and reproductive biology of humans and animals. 5th edition. Springer Spectrum, 2012.
  3. ↑ a b c Michael E. Zuber, Gaia Gestri, Andrea S. Viczian, Giuseppina Barsacchi and William A. Harris: Specification of the vertebrate eye by a network of eye field transcription factors. In: Development. 12/2003, 130, pp. 5155-5167.
  4. ↑ a b Georg Halder, Patrick Callaerts, Walter J. Gehring: Induction of Ectopic Eyes by Targeted Expression of the eyeless Gene in Drosophila. In: Science. 267 (1995), pp. 1788-1792.
  5. ^ A b Robert L. Chow, Curtis R. Altmann, Richard A. Lang, Ali Hemmati-Brivanlou: Pax6 induces ectopic eyes in a vertebrate. In: Development. 126, 1999, pp. 4213-4222.
  6. ↑ D. Uwanogho, M. Rex, EJ Cartwright, G. Pearl, C. Healy, PJ Scotting, PT Sharpe: Embryonic expression of the chicken Sox2, Sox3 and Sox11 genes suggests an interactive role in neuronal development Mech. In: Development. 49 (1995), pp. 23-36.
  7. ↑ Reinhard W. Köste, Ronald P. Kühnlein, Joachim Wittbrodt: Ectopic Sox3 activity elicits sensory placode formation. In: Science direct. Volume 95, Issues 1-2, July 1, 2000, pp. 175-187.
  8. ↑ a b c Michael Kühl, Susanne Gessert: Developmental Biology . UTB Basics, 2010.
  9. ↑ Désirée White, Montserrat Rabago-Smith: Genotype-phenotype associations and human eye color. In: Journal of Human Genetics. 56, 5-7 (January 2011).
  10. ↑ Jesper Kronhamn, Erich Frei, Michael Daube, Renjie Jiao, Yandong Shi, Markus Noll, Åsa Rasmuson-Lestander: Headless flies produced by mutations in the paralogous Pax6 genes eyeless and twin of eyeless. In: Development. 129, 2002, pp. 1015-1026.
  11. ↑ MA Serikaku, JE O'Tousa: Sine oculis is a homeobox gene required for Drosophila visual system development. In: Genetics. 1994 Dec; 138 (4), pp. 1137-1150.
  12. ^ Nancy M. Bonini *, Quang T. Bui, Gladys L. Gray-Board, John M. Warrick: The Drosophila eyes absent gene directs ectopic eye formation in a pathway conserved between flies and vertebrates. In: Development. 124, 1997, pp. 4819-4826.
  13. ↑ TA Heanue, RJ Davis, DH Rowitch, A. Kispert, AP McMahon, G. Mardon, CJ Tabin: Dach1, a vertebrate homologue of Drosophila dachshund, is expressed in the developing eye and ear of both chick and mouse and is regulated independently of Pax and Eya genes. In: Mech Dev. 2002 Feb; 111 (1-2), pp. 75-87.
  14. ↑ Chin Chiang, Ying Litingtung, Eric Lee, Keith E. Young, Jeffrey L Corden, Heiner Westphal, Philip A. Beachy: Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. In: Nature. 383 (6599) (1996), pp. 407-413. doi : 10.1038 / 383407a0 . PMID 8837770
  15. ^ A b M. Rembold, F. Loosli, RJ Adams, J. Wittbrodt: Individual cell migration serves as the driving force for optic vesicle evagination. In: Science. 2006 Aug 25; 313 (5790), pp. 1130-1134.
  16. ↑ A wandering eye. The Biotechnology and Life Sciences Portal Baden-Württemberg 2006 ( Memento from September 26, 2013 in the Internet Archive )
  17. ↑ a b R. M. Grainger: Embryonic lens induction: Shedding light on vertebrate tissue determination. In: Transgenic. 8, 1992, pp. 349-355.
  18. ↑ Bertram Schnorr, Monika Kressin: Embryology of Pets. 6th edition. Enke.
  19. ↑ Nick Lane: Life - Amazing Inventions of Evolution. Cape. 7: See . Primus Verlag, 2013.
  20. ↑ Fascination with the life sciences. Wiley-VCH, 2002.
  21. ↑ Renate Lüllmann-Rauch, Friedrich Paulsen: Taschenbuch der Histologie. 4th edition. Thieme, Stuttgart.
  22. ↑ Égouchi, Goro et al. Regenerative capacity in newts is not altered by repeated regeneration and aging. Nature Communication, 2011, July 2, 384
  23. ^ Leon S. Stone: Regeneration of the Lens, Iris, and Neural Retina in a Vertebrate Eye. In: Yale J Biol Med. 1960 June; 32 (6), pp. 464-473.
  24. ^ A b S. W. Wang, X. Mu, WJ Bowers, WH Klein: Retinal ganglion cell differentiation in cultured mouse retinal explants. In: Methods. 2002 Dec; 28 (4), pp. 448-456.
  25. ↑ MJ Belliveau, CL Cepko: Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina. In: Development. 1999 Feb; 126 (3), pp. 555-566.
  26. ^ CJ Neumann, C. Nüsslein-Volhard : Patterning of the zebrafish retina by a wave of sonic hedgehog activity. In: Science. 289 (5487), pp. 2137-2139.
  27. ↑ Alena Shkumatava, Sabine Fischer, Ferenc Müller, Uwe Strahle, Carl J. Neumann: Sonic hedgehog, secreted by amacrine cells, acts as a short-range signal to direct differentiation and lamination in the zebrafish retina. In: Development. 131, 2004, pp. 3849-3858.
  28. ^ SJ Isenberg: Macular development in the premature infant. In: Am J Ophthalmol. 1986 Jan 15; 101 (1), pp. 74-80.
  29. ↑ Linda Conlin: Embryonic Eye Development. Nov 2012
  30. ^ W. Westheide; RM Rieger; G. Rieger; G. Rieger (Ed.): Special zoology. Part 2: vertebrates or skulls. 2nd Edition. Springer Verlag, 2010, ISBN 978-3-8274-2039-8 , p. 100.
  31. ↑ Johannes W. Rohen, Elke Lütjen-Drecoll: Functional Histology. 4th edition. Schattauer, FK Verlag, 2000, ISBN 3-7945-2044-0 , p. 476.
  32. ↑ Jan Zrzavý, Hynek Burda, David Storch, Sabine Begall, Stanislav Mihulka: Evolution: A reading textbook . 2nd Edition. Springer Verlag, Berlin, Heidelberg 2013, ISBN 978-3-642-39695-3 , pp. 258 .
  33. ↑ a b c R.W. Sperry: Chemoaffinity in the Orderly Growth of Nerve Fiber Patterns and Connections. In: Proc. Natl. Acad. Sci. (USA), 50, pp. 703-710 (1963).
  34. ^ DD O'Leary, DG Wilkinson: Eph receptors and ephrins in neural development. In: Curr Opin Neurobiol. 1999 Feb; 9 (1), pp. 65-73.
  35. ↑ M. Jacobson: Retinal ganglion cells: specification of central connections in larval Xenopus laevis. In: Science. 1967 Mar 3; 155 (3766), pp. 1106-1108.
  36. ↑ after Wolfgang Maier: head. In: W. Westheide, R. Rieger (Ed.): Special Zoology. Part 1: Protozoa and invertebrates. Gustav Fischer, Stuttgart / Jena 1997, 2004, ISBN 3-8274-1482-2 , p. 32.
  37. ↑ Hildebrand, Milton and Goslow, George: Comparative and functional anatomy of the vertebrates. English original edition published by John Whiley & Sons, USA, 2001, ISBN 3-540-00757-1 , p. 204 ff.
  38. ↑ Jan Langman (original), Thomas W. Sadler: Medical Embryology. Normal human development and its malformations. 10th edition. Thieme Verlag, Stuttgart 2003, ISBN 3-13-446610-4 , p. 172 ff.
  39. ^ Herbert Kaufmann: Strabismus. 4th fundamentally revised and expanded edition. with the collaboration of W. de Decker u. a. Georg Thieme Verlag, Stuttgart / New York 2012, ISBN 978-3-13-129724-2 .
  40. ↑ Inge Flehmig: Normal development of babies and their deviations: early detection and early treatment . Georg Thieme Verlag, 2007. ISBN 9783135606071
  41. ^ A b Walther Grauman, Dieter Sasse: Compact textbook of the entire anatomy 04 : Sensory systems, skin, CNS, peripheral pathways. 1st edition. Volume 4, Schattauer Verlag, 2004, ISBN 3-7945-2064-5 .
  42. ↑ a b Martina Ibounigg: Special Embryology . GRIN Verlag, Munich 2001, ISBN 3-638-98508-3 , doi : 10.3239 / 9783638985086
  43. ^ RW Dudek, JD Fix: Eye. In: Embryology - Board Review Series. 3. Edition. Lippincott Williams & Wilkins, 2004, ISBN 0-7817-5726-6 , p. 92.
  44. ^ A b Sujata Rao, Christina Chun, Jieqing Fan, J. Matthew Kofron, Michael B. Yang, Rashmi S. Hegde, Napoleone Ferrara, David R. Copenhagen, Richard A. Lang: A direct and melanopsin-dependent fetal light response regulates mouse eye development. In: Nature. 494, pp. 243-246 (February 14, 2013)
  45. ^ Herbert Kaufmann: Strabismus . 4th fundamentally revised and expanded edition. with the collaboration of W. de Decker u. a., Georg Thieme Verlag, Stuttgart / New York 2012, ISBN 978-3-13-129724-2 .
  46. ↑ Barbara Käsmann-Kellner: Development of Vision in Childhood - Amblyopia and Screening ( Memento from October 29, 2013 in the Internet Archive ) University Eye Clinic Homburg. (PDF; 3.8 MB)
  47. ↑ G. Bargsten: Persistent remnants of the pupillary membrane in adult rats of different strains . Zeitschrift für Laborstierkunde, 30 (1987), pp. 117-121.
  48. ↑ Paul Simoens: organ of sight, Organum visus. In: Franz-Viktor Salomon, Hans Geyer, Uwe Gille (Ed.): Anatomy for veterinary medicine. 2nd, revised and expanded edition. Enke, Stuttgart a. a. 2008, ISBN 978-3-8304-1075-1 , pp. 579-612.
  49. ↑ O.-E. Lund, B. von Barsewisch: The macula in the animal series. Macular diseases. In: German Ophthalmological Society. Volume 73, 1975, pp. 11-17. Jumper
  50. ↑ SG Kiama, JN Maina, J. Bhattacharjee, KD Weyrauch: Functional morphology of the pecten oculi in the nocturnal spotted eagle owl (Bubo bubo africanus), and the diurnal black kite (Milvus migrans) and domestic fowl (Gallus gallus var. Domesticus ): a comparative study. In: Journal of Zoology. 254 (2001), pp. 521-528.
  51. ↑ Timothy H. Goldsmith, Birds See the World as More Colorful. In: Spectrum of Science. January 2007, pp. 96-103; → Spectrum and (PDF)
  52. ↑ a b c Georg Glaeser, Hannes F. Paulus : The evolution of the eye. Springer Spectrum 2014.
  53. ↑ Kenneth T. Brown: A linear area centralis extending across the turtle retina and stabilized to the horizon by non-visual cues. In: Vision Research. 10/1969; 9 (9), pp. 1053-1062.
  54. ^ A. Herrel, JJ Meyers, P. Aerts, KC Nishikawa: The Mechanics of prey prehension in chameleons. In: Journal of Experimental Biology. 203 (2000), pp. 3255-3263.
  55. ^ Aristotels, Natural History of Animals; 3: Book 6-8, Vol.6, Nabu Press 2012 ( Historia animalium )
  56. ↑ Horst Seidl: Contributions to Aristotle's natural philosophy. (= Elementa texts. 5). Editions Rodopi, 1995, p. 146.
  57. ↑ Carolin M. Oser-Grote: The eye and the process of seeing in Aristotle and the Hippocratic writing De carnibus. In: Wolfgang Kullmann (Ed.): Aristotelian Biology: Intentions, Methods, Results. Steiner, Stuttgart 1997, ISBN 3-515-07047-8 , p. 339.
  58. ↑ Carolin M. Oser-Grote: The eye and the process of seeing in Aristotle and the Hippocratic writing De carnibus. In: Wolfgang Kullmann (Ed.): Aristotelian Biology: Intentions, Methods, Results. Steiner, Stuttgart 1997, ISBN 3-515-07047-8 , p. 340.
  59. ^ Gustav Wolff: Developmental Physiological Studies. Part I: The regeneration of the urodele lens. In: Roux Arch. Entw. Mech. Org. 1, pp. 280-390.
  60. ^ AK Knecht, M. Bronner-Fraser: Induction of the neural crest: a multigene process. In: Nat Rev Genet. 2002 Jun; 3 (6), pp. 453-461.
  61. ↑ A wandering eye. The Biotechnology and Life Sciences Portal Baden-Württemberg 2006 ( Memento from September 26, 2013 in the Internet Archive )
  62. ↑ Paola Betancur, Marianne Bronner-Fraser, Tatjana Sauka-Spengler: Assembling Neural Crest Regulatory Circuits into a Gene Regulatory Network. In: Annual Review of Cell and Developmental Biology. Vol. 26, pp. 581-603.
This article was added to the list of excellent articles on November 26, 2013 in this version .