GENETIC BACKGROUND of the DEVELOPMENT of the EYE during the period
of EMBRYOGENESIS
The genetic control of the development of the eye takes place during the whole course of the development but is more crucial during the Stage of Embryogenesis.Each stage of development is under the control of specific genes. As early as the cleavage of the morula, a group of pluripotent embryonic cells acquires the capacity to form retinal cells, the RETINAL STEM cells and a 70 KDa Heat Schock Protein is expressed; this Heat Schock Protein continues to be expressed during the whole embryonal and fetal development of the eye and plays a role in the protection of the embryo. At the stage of induction of the NEURAL PLATE, the BONE MORPHOGENETIC PROTEIN (BMP) and the WINGLESS Related Mouse Mammary Tumor Virus Integration on site (WNT) genes are very active. In addition to the signaling pathways of the BMP and WNT, FIBROBLASTIC GROWTH FACTORS (FGFs)are required for mesoderm formation from the epiblast and caudalization of the neural plate. Moreover, a Zinc Finger DNA binding protein called CHURCHILL (ChCh) which is expressed first in the prospective neural plate and continues to be expressed in the forming neural plate, also plays a role; its transcripts, present also in the epiblast adjoining the primitive streak, prevent the epiblast of forming more mesoderm. A number of transcription factors are expressed in the development of the anterior neural plate. The factor encoded by the OTX2 gene is essential for neural induction, while the factors encoded by SIX3, HESH1/RPx, Rx and Pax genes are essential for the normal development of the eye. The gene Rx which is expressed initially in the anterior neural region is also expressed later in the retina and ventral hypothalamus. Its importance is emphasized by the fact that mutation in this gene causes ANOPHTHALMUS. Once the Neural Plate is induced, its lateral borders elevate into NEURAL FOLDS which move towards the midline, to fuse and form the NEURAL GROOVE first and the NEURAL TUBE after Fusion. Several genes were shown to be involved in the regulation of the neural tube formation: 1-The transcription factor T gene encodes a protein which binds DNA to a specific motif called the T Bo and is involved in mesoderm development. 2-The tumor suppressor BRCA gene encodes a transcription factor which inhibits the proliferation of epithelial cells and gives a signal to the neuroepithelial cells to proliferate. 3-The family of Pax genes encode transcription factors which play a key role in the normal embryological development. 4-The Platelet Derived Growth Factor Receptor (PDGFR) gene is related to the neurulation process. After the formation of the neural Tube , organizing centers appear around it. These centers are groups of cells which send signals to form the Progenitor neurons. Two organizing centers are located in the neural tube floor and in the Notochord beneath. Other centers are located in the forming neural folds and in the roof of the neural tube. The progenitor cells of the floor are accredited with the pattern of neurons in the Ventral Central Nervous System (CNS), while those from the roof, with the pattern of neurons in the Dorsal CNS. Signals traveling to the epidermis above the neural tube, prior to its closure,induce the formation of NEURAL CREST CELLS. This induction causes a transition of epithelial cells into mesenchymal cells, which are the precursor of neural crest cells. BMP and WNT are among the signals which induce the formation of neural crest cells. Migrating neural crest cells intermingle with mesodermal cells on both sides of the neural tube and form the secondary mesoderm. The Pax genes are expressed in a speciific spatial and temporal pattern during development. They encode transcription factors which regulate the normal development of the embryo. The proteins encoded by the Pax genes are defined by the presence of a 128- aminoacid DNA binding domain, the paired domain (PD) which makes sequence specific contacts with DNA and is located near the amino(NH 2) terminus, of a paired type homeo-domain (HD) also binding DNA and of a 8 aminoacid domain (octopeptide) located between the PD and the HD and possessing a transcriptional inhibitory activity. The family of Pax genes consists of 9 members designated Pax 1 to Pax 9; they are classified into 6 classes: Pax 1 is expressed in the sclerotome; its mutation causes skeletal defects. Pax 3 is expressed in the somites, neural tube and neural crest cells; its mutation causes the Waardenburg syndrome. Pax 6 is specially expressed in the optic cup, retina, lens and cornea during the development of the eye and its mutation causes ANIRIDIA. Pax 2 is expressed early in the development of the eye and in the kidney; its mutation causes eye and kidney malformation. Pax 3 and Pax 7 might be involved in chromosomal translocations which putatively play a role in the appearance of rhabdomyosarcoma. In the eye, Pax 2 and Pax 6 share overlapping domains of expression in the Optic Vesicle. Later on, Pax 2 is restricted to the Optic Stalk where it labels the Optic nerve and Pax 6 is expressed in the prospective Outer Retinal Layer. Pax 2 expression establishes a boundary between itself and the expression of Pax 6; this boundary is present between the prospective optic nerve and the prospective outer retinal layer. Outside the nervous system, Pax genes are involved in cellular differentiation processes whete epithelial-mesenchymal transitions take place.