For the growth and development of all multi-cellular organisms, the key aspect is the effective intercellular communication within them. For the formation of the primary and structural body pattern in animals, secretion of the hedgehog (hh) protein takes place which is essential for both long and short-range cellular signalling and coordination. First studied in Drosophila melanogaster (fruit flies), the hedgehog gene got its name from the data that during the embryonic development of flies, their mutated version very evidently resembles a spiky hedgehog.
Typically, the molecular evolutionary studies have indicated that the vertebrate homologs of the Drosophila (hh) gene arose by two gene duplications: the first one giving rise to Desert (Dhh), and the second one giving Sonic (Shh) and Indian (Ihh) gene. Although most studies have been performed with Shh, all the three work similarly, but in different contexts.
Talking first of the best studied and the most important ligand of the hegdehog gene Family, the Sonic Hedgehog gene was first identified in the classic Heidelberg screens of Eric Wieschaus and Christiane Nusslein-Volhard, which was then published in the year 1978. Basically, the gene derived its name after the Sega's videogame character, Sonic the Hedgehog. Being the best example of a morphogen, these genes control the segmentation patterns of Drosophila melanogaster (fruit fly) embryos.
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The Sonic Hedgehog gene is seen both in embryos as well as in adults, especially with its thriving importance in the signalling pathway. In the embryo, this gene is secreted by the zone of polarizing activity (ZPA), which is located on the posterior side of a limb bud within the embryo. However, in adults, it is thoroughly expressed in the Neural tube floorplate, the Hensen Node, the early gut Endoderm, the posterior of the limb buds and the Notochord.
This Hedgehog gene has a very peculiar structure. Its precursor form is essentially divided into an N-terminal (Shh-N) and a C-terminal (Shh-C) domain. During the process of catalysis, Shh-N gets covalently attached to a molecule of cholesterol, and the formation of this complex performs the signalling functions. Shh-C is responsible for the attachment of cholesterol and carrying out the cleavage reaction. Shh-N, then binds itself to the Trans-membrane protein Patched (Ptc). This results in the depression of a Ptc- interacting membrane protein called Smoothened (Smo), which further causes the activation of GLI, a transcription factor. This factor is believed to control the ultimate expression of the nuclear targets of Sonic Hedgehog.
Proceeding to the next two hedgehog genes, Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), it is quite evident that there is not much being studied in that sector. However, they work and function very closely related to the Sonic Hedgehog (Shh) gene. The Indian Hedgehog (Ihh) protein is mainly involved in the Chondrocyte differentiation, proliferation and maturation during the Endochondral Ossification. Its actions are regulated by the parathyroid hormone-related peptide. The Desert Hedgehog (Dhh) gene is mainly involved in encoding signalling molecules that play an important role in the process of morphogenesis. This gene has also been seen to be involved in the male gonadal differentiation and per neural development. Its structure and process of catalysis are eminently similar to that of the Shh.
Out of the three derived Hedgehog genes, Sonic Hedgehog (Shh) gene has the most critical roles in growth and development. As mentioned earlier, it acts as a morphogen, involved in patterning many body systems and regulating vertebrate organogenesis (process of the development of ectoderm, endoderm and mesoderm into the internal organs of an organism). This includes growth in the digits on limbs and organisation of brain comprising of midline structures in the brain and spinal cord, and thalamus. These genes also control the cell division process in adult stem cells and its transcription pathway has been implicated in the formation of various specific kinds of cancerous tumours. The Sonic Hedgehog (Shh) gene has also been proved to be acting as an axonal guidance cue (axon path finding wherein the neurons send out axons to their specific targets during the subfield stages of Neural development).
Defects in Hedgehog gene signalling could affect both the adult as well as the human embryo, as it contains proteins and signal-transduction components which are expressed in both stages. The abnormalities in the Shh signalling often leads to several genetic syndromes, including holoprosencephaly, Smith-Lemli-Opitz syndrome, Gorlin's Syndrome, Pallister-Hall syndrome, deregulation of the bone growth et al. An over-activity of the Shh signalling pathway in post-natal life stage also results in several cancers like breast, basal cell, rhabdomyosarcoma, glioblastoma and osteosarcoma. The irregularities in the Shh signalling also leads to several defects in the other organisms like frogs and mice, including basal cell carcinomas, cyclopia and multiple defects in heart and gut, exencephaly, brain tumours et al.
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Since the Hedgehog pathway is a highly guarded signalling cascade involving numerous developmental processes, its role in adult is still less well-established. However, this signalling pathway is seen to get activated and reutilised under the circumstances of repair and regeneration. This has, by far been proved as the most outstanding and new approach to treating neurodegenerative diseases and their dysfunctions including spinal cord injury.
Hence, with the aforementioned data, it is clearly portrayed that the Hedgehog (hh) gene and its pathway signalling is not only important in humans, but it also is an essentially consequential process in the growth and development of the other organisms. Hedgehog gene mutations could lead to anything from defects in the limb developments, cyclopia, to even death as a matter of fact. However, with the advancement of the developmental Biology and its growing era, more research is contrived and discoveries are made, which results in this gene, its functions and uses being implicated in various other parts of development as well.