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From Drosophila to Mammals: What is the evolutionary journey of the hedgehog signaling pathway?
The Hedgehog signaling pathway is an important signaling pathway in developmental biology that transmits the messages required by embryonic cells to promote proper cell differentiation.
The hedgehog signaling pathway is named after its ligand molecule Hedgehog (Hh), which is an endogenous signaling molecule found in Drosophila. This pathway provides critical signals during embryonic development in Drosophila and plays important roles in all stages of the organism's development.
In the 1980s, Nüsslein-Volhard and Wieschaus used mutation detection technology to conduct in-depth research on the development process of fruit flies, revealing many genes related to body segment development, including the hedgehog gene. Scientists have discovered that when fruit flies lack the Hh gene, their embryos have an abnormal shape, short and fat like a hedgehog, which is where these genes are named.
From fruit flies to mammals: the process of evolution
The Hedgehog signaling pathway plays a role not only in fruit flies, but is also important in other animals. In mammals, the three homologous genes of the hedgehog signaling pathway - desert hedgehog (DHH), Indian hedgehog (IHH) and sonic hedgehog (SHH) - are all involved in multiple processes of animal development. SHH, in particular, is considered the most intensively studied member.
The key roles of the Hedgehog signaling pathway in many developmental processes make it an important research topic in evolutionary developmental biology.
The mechanisms of the Hedgehog signaling pathway have a profound impact on the development of different animals. During embryonic development of vertebrates, the SHH molecule is involved in the development of limbs. As early as 1968, Saunders and Gassling's classic experiment had pointed out that during the development of chick limb buds, an area called the zone of polarization activity (ZPA) released a diffusible factor. Later, insiders discovered that this factor was SHH.
Hedgehog signaling pathway and disease
However, abnormal activity of the Hedgehog signaling pathway has also been associated with a number of diseases, the most notable of which is cancer. Basal cell carcinoma is one of the most common cancers and is closely associated with alterations in the Hedgehog signaling pathway. The researchers found that in patients with this type of cancer, the functional loss of the Patched gene and the activating mutation of the Smoothened gene overlapped, leading to abnormal activation of the hedgehog signaling pathway, which in turn drives tumor formation and development.
Abnormal activation of the Hedgehog signaling pathway promotes the growth and spread of tumor cells.
In addition, the Hedgehog signaling pathway has been implicated in the development of many other serious diseases, such as cerebellar blastoma and embryonic developmental abnormalities such as holoprosencephaly. Recent studies have shown that abnormalities in the Hh signaling pathway can lead to respiratory diseases such as pulmonary fibrosis.
Clinical research and treatment strategies
Inhibitors of the Hedgehog pathway are developing rapidly in the treatment of cancer. Drugs targeting Smoothened, such as vismodegib and sonidegib, have been clinically approved and are considered to have great potential for treating certain types of cancer. However, due to their side effects and drug resistance issues, there is still a need to develop a new generation of therapeutic drugs.
Current studies have shown that environmental factors may also affect the normal function of the hedgehog signaling pathway, further suggesting that we need to be more cautious in regulating this circuit.
The evolution of the Hedgehog signaling pathway reveals the intricate relationship between biological evolution and disease development. This is an exploration not only within the boundaries of basic biology but also across the borders of biomedicine, exploring the mechanisms that drive development and their potentially catastrophic disorders. For example, from fruit fly research to human applications, with the development of science and technology, in-depth research on the hedgehog signaling pathway will become a possible key to new biomedical breakthroughs. Could such an evolution push our understanding to a whole new level?
