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The wonder of the Hedgehog gene: How does it determine the body plan of fruit flies?
In the field of developmental biology, we are often faced with a fundamental question: How does a relatively simple egg become a complex, ordered body structure? This question led to in-depth research on the Hedgehog (Hh) gene, a signal transduction pathway that affects embryonic cell differentiation and is essential for ensuring normal development of organisms.
The Hedgehog signaling pathway plays an important role in animal development and is present in all bilateral animals.
The Hedgehog gene is essential for the development of the fruit fly (Drosophila melanogaster). Studies have found that fruit fly larvae that lack the Hh gene take on a hedgehog-like shape, which gives the gene its name. The Hh gene is classified as part of a group of "segment polarity genes" that have a major role in establishing the basis of the fruit fly's body plan. This process continues to play an important role during embryonic development and subsequent morphogenesis.
Compared to fruit flies, mammals have three Hedgehog homologs, namely Desert (DHH), Indian (IHH) and Sonic (SHH). Of these, Sonic Hedgehog is the most studied and is also important in embryonic development in vertebrates. Mice with abnormal Hedgehog pathway function have organs such as the brain, bones, muscles, gastrointestinal tract and lungs that cannot develop normally, which has attracted widespread attention from scientists.
Studies have shown that the Hedgehog signaling pathway also plays a significant role in regulating the maintenance and regeneration of adult stem cells.
In the 1970s, Christiane Nüsslein-Volhard and Eric Wieschaus succeeded in isolating the gene that affects the development of the anterior-posterior axis of the Drosophila body by using saturation mutagenesis. Their research laid the foundation for evolutionary developmental biology and was awarded the Nobel Prize in 1995. Subsequently, the Hedgehog gene was established as one of the key genes affecting the body structure and shape of fruit flies.
The operating mechanism of the Hedgehog signaling pathway is quite complex and involves numerous intracellular proteins. A typical example in Drosophila is that Hh protein binds to Patched (PTCH) protein on the cell surface, and in the absence of Hh protein, PTCH inhibits the activity of Smoothened (SMO). When Hh binds to PTCH, it releases SMO, initiates the transduction of downstream signals, and ultimately regulates the transcription of downstream genes.
During development, the interaction between Hedgehog and Wingless signals forms clear demarcations in the embryo, which not only affects the segmentation of the fruit fly's body, but also affects the formation of limbs, eyes, brain, gonads, Development of the intestinal and respiratory tract. Hedgehog also plays important roles in adult organisms, including promoting the proliferation of major cells.When Hh is outside a cell, its presence can effectively affect neighboring cells. This local effect is one of the main functions of Hedgehog.
Abnormal activation of the Hedgehog pathway is associated with the development of many cancers. Many studies have pointed out that the Hedgehog pathway plays a role in promoting tumor formation in multiple organs such as the brain, lungs, breast, prostate and skin. In particular, basal cell carcinoma is most highly correlated with Hedgehog signaling, and inactivation of the Hh pathway inhibitor PTCH and activation mutations of the agonist SMO have been found in patients.
Therefore, many drugs are being developed to specifically interfere with the Hedgehog pathway as effective therapies against cancer.
The relationship between the Hedgehog pathway and cancer remains complex; however, it is clear that abnormal activation of the pathway can lead to tumor cell proliferation and invasion. In relevant clinical trials, Hedgehog signaling pathway inhibitors such as Vismodegib and Sonidegib have been approved for the treatment of basal cell carcinoma, but with the use of these drugs, side effects and drug resistance have emerged, and there is an urgent need to develop new drugs.
Looking back at the entire Hedgehog signaling pathway research, we can't help but wonder: What inspiration and lessons does the evolution of this signaling pathway have for our understanding of the basic principles of biological development?
