Organogenesis Proteins

 Organogenesis Proteins Background

Organogenesis is the process during which the internal organs are developed from the three germ layers composed of ectoderm (outer), mesoderm (middle), and endoderm (inner). During organogenesis, three different types of morphological changes which change the form of an organism take place, including folds, splits, and dense clustering during the third to eighth week of gestation. Organogenesis is consisting of a series of complex events and involves the coordination of multiple developmental processes. For example, it is associated with cell proliferation and differentiation, embryonic induction, morphogenesis and pattern formation. The embryonic stem cells will express specific genes and these genes will influence which cell type they are going to be.

In organogenesis of vertebrates, the neural system will be primary developed by the ectoderm, which also forms epithelial cells and tissues. Studies show that some cells at the edge of the ectoderm develop into epidermis cells, and the remaining cells at the center develop into the neural plate. The neural plate will form neural tube and further develop into the brain and the spinal cord.

The mesoderm will develop into kinds of connective tissues of the animal body or cells called somites. The somites can further develop into many tissues or organs such as lungs, ribs, and spine muscle. The notochord, forming the central axis of the animal body, is also developed from the mesoderm.

The endoderm develops into the epithelial lining of the digestive tube and the terminal part of the rectum. In addition, the endoderm also develops into the lining cells of all the glands opening into the digestive tube, such as liver, pancreas, the stomach and the colon. Additionally, endoderm forms other organs like the urinary bladder, thyroid gland and thymus. The endoderm is also important for respiratory system, forming the bronchi, trachea and air cells of the lungs.


Vessel Development

Establishment of the vasculature during embryogenesis involves two distinctive processes: vasculogenesis and angiogenesis. Vasculogenesis occurs when new blood vessels are generated de novo from blood islands in a highly regulated manner, while angiogenesis involves the formation of new blood vessels from preexisting vasculature. The generation of the primary capillary plexus by vasculogenesis follows four important steps: 1) the generation of angioblasts; 2) angioblast aggregation and assembly into tube-like forms; 3) the construction of vessel lumens; and 4) the establishment of vascular networks. The primary vasculature undergoes continuous remodeling into mature circulatory vessels by angiogenesis.

Angiogenesis is not only a required event during embryogenesis for the establishment of blood vessel networks and the circulatory system, but is also found in many pathological events in adults, such as rheumatoid arthritis, psoriasis, tumorigenesis, and diabetic retinopathy. Angiogenesis can be roughly divided into two phases: the activation phase and the maturation phase. In the activation phase, endothelial cells (ECs) migrate into the extracellular space by penetrating the peri-vascular basement membrane. They continue to proliferate and form capillary sprouts and tubular structures. In the maturation phase, ECs stop migration and proliferation to reconstitute a basement membrane and vessel wall by the recruitment of smooth muscle cells. During this highly regulated process, a balance between pro- and anti-angiogenic factors regulates the sequential steps of angiogenesis. Several growth factors are considered to be pro-angiogenic in this process, including basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta 1 (TGF-β1). Since ECs are essential components of angiogenesis, the abilities of these growth factors to stimulate angiogenesis are tightly associated with their effects on ECs. For example, VEGF-C is able to promote the migration and proliferation of ECs in vitro and in vivo. To illustrate the regulation of individual growth factor pathways and the cooperation among these angiogenic factors in angiogenesis is an area of study with much to be learned.


Lung Morphogenesis

Normal embryonic development of lung is essential to initiate and maintain the oxygen exchange after birth. In mouse, lung formation initiates at embryonic day 9.5 (E9.5) as a pair of primary buds that are formed with foregut originated endoderm evaginated from the laryngotracheal groove into the surrounding splanchnic mesenchyme. Early lung development can be divided into four stages. First, the bronchial and respiratory bronchiole tree is formed during the pseudoglandular stage (E9.5- E16.6). Second, at the canalicular stage (E16.6- E17.4), the distal epithelium and mesenchyme undergo extensive branching into terminal sacs adjacent to the mesoderm-derived capillaries. Third, terminal sacs and vasculature are further developed along with the maturation of alveolar epithelial type I and II cells during the terminal sac stage [E17.5 to postnatal day 5 (P5)]. Lastly, the alveolar stage (P5 to P30) is characterized by differentiation of the terminal respiratory sacs into alveolar ducts and sacs.

The mature respiratory system is composed of different types of epithelial cells. The location along the proximal to distal airway determines the type of epithelial cells. The larynx is lined with squamous epithelial cells. The upper airways are characterized by a mixture of ciliated columnar and mucus-secreting goblet cells with clusters of pulmonary neuroendocrine cells (PNECs). The primary bronchioles contain clara cells, which are important for detoxifying harmful substances. The terminal alveolar sacs are composed of two types of epithelial cells. Type I epithelial cells enable gas exchange with the circulation by forming tight junctions with the pulmonary endothelial cells. Type II epithelial cells secrete surfactant proteins, which are essential to reduce surface tension of alveoli and facilitate their expansion.

Many growth factor pathways are involved in lung branching morphogenesis and epithelial cell differentiation. For example, genetic deletion of fibroblast growth factor 10 (Fgf10) in the lung mesenchyme or FGF10 receptor (Fgfr2IIIb) in the epithelium lead to severe pulmonary agenesis, which indicates the essential role of the FGF pathway in early lung morphogenesis. Another important growth factor is sonic hedgehog (SHH). Several human congenital pulmonary defects have been related to abnormalities in the SHH signaling. The Shh deficient lungs display a hypoplastic phenotype, missing distal lung tissues, and delaying type II epithelial cell differentiation.


Cardiac Development

Congenital heart diseases are among the most common human birth defects, and occur in approximately 1% of the newborn population. Two major forms of these malformations are cardiac septation defects and valvular anomalies, which are related to problems in cardiac cushion formation and valve development. At E8.0, the mouse heart has a tubular structure formed by a myocardial outer layer and an endocardial inner layer. The linear heart tube undergoes elongation and looping to generate these major components from anterior to posterior, including outflow tract (OFT), primitive ventricle, atrioventricular canal (AVC), atria and inflow tract. Following the looping of heart, ECs in the AVC and OFT start an epithelial-to-mesenchymal transformation (EMT) to form the AVC cushions located between the future atria and ventricle around E9.5, and to contribute to the endocardial ridges at the OFT slightly later. The OFT is closed to separate the aorta from the pulmonary trunk by the fusion of the endocardial ridges. These cushion formations result in left to right separation of the heart.

Another important event for heart formation is valvulogenesis. Cardiac valves start to develop along with the endocardial cushion formation at the AVC and OFT region during the looping stage at E9.5. Within the endocardial cushions undifferentiated heart valve progenitor cells first undergo proliferation followed by the remodeling stage, including decreased proliferation and production of extracellular matrix layers abundant in collagen, elastin and proteoglycan. At the end, endocardial ridges contribute to the semilunar valves located in the aorta and pulmonary artery, while the leaflets of the mitral and tricuspid valves are derived from the AVC cushion and direct the blood flow from atria to ventricles.


Organogenesis related references

1. Mebius R E. Organogenesis of lymphoid tissues[J]. Nature Reviews Immunology, 2003, 3(4): 292-303.

2. Sheng H Z, Moriyama K, Yamashita T, et al. Multistep control of pituitary organogenesis[J]. Science, 1997, 278(5344): 1809-1812.

3. Pispa J, Thesleff I. Mechanisms of ectodermal organogenesis[J]. Developmental biology, 2003, 262(2): 195-205.