14.3 : Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to perform specialized functions in different developmental processes in mammals. Additionally, unlike in invertebrate Hh signaling, mammalian Hedgehog signaling is also reliant upon a microtubule-based organelle called the primary cilium that is present on the cell surface of most vertebrate cells.

The Hedgehog Signaling Mechanism

The Hedgehog gene encodes for the Hedgehog precursor protein, which undergoes significant posttranslational modifications inside the endoplasmic reticulum. These lipid modifications of the Hedgehog protein play an essential role in the secretion of the active Hedgehog ligand from the signaling cell and its migration to the target cells. In the absence of active Hedgehog ligand, the Patched protein present on the target cell surface is the primary inhibitor of the downstream Hedgehog signaling. However, when the active Hedgehog ligand binds to the Patched protein, another transmembrane protein called Smoothened translocates to the cell surface. The Smoothened protein is then able to interrupt the activity of a multiprotein microtubule-associated complex in its degradation of Cubitus Interruptus. Cubitus Interruptus is the primary transcriptional activator in the Hh signaling pathway and subsequently translocates to the nucleus to turn on the expression of Hh target genes.

Functions and Associated Diseases

Hh signaling is crucial for organ development, and any disruptions to Hh during embryogenesis can lead to severe developmental abnormalities. Additionally, Hh signaling is essential for stem cell regeneration, which is responsible for the maintenance and regeneration of adult tissues. Abnormalities in the Hh signaling pathway can, therefore, lead to certain types of cancer, including pancreas, lung, prostate, breast, and brain tumors. Because of this, the Hh gene and signaling pathway is a valid therapeutic target for the pharmaceutical industry.